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tumor immunotherapy has been expected to become a new approach in the field of tumor therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> CD8<span class="elsevierStyleSup">&#43;</span>T cells are the most important regulatory cells in tumor-acquired immunity&#44; which mediates anti-tumor immunity by directly killing cancer cells&#44; so activation of CD8<span class="elsevierStyleSup">&#43;</span>T cells may be the key to immunotherapy for cSCC&#46; Studies have shown that Programmed Death ligand-1 &#40;PD-1&#41; is highly expressed in CD8<span class="elsevierStyleSup">&#43;</span>T cells in cSCC and blocking PD-1 with monoclonal antibody is one of the effective methods&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> PD-1 inhibitors can block the binding of PD-1 and PD-L1&#44; resulting in the transduction of immunosuppressive signals in the PD-1&#47;PD-L1 pathway&#44; and then restore and promote the immune killing function of CD8<span class="elsevierStyleSup">&#43;</span>T cells&#44;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;13</span></a> making them play a powerful anti-tumor role&#46; It has been reported that the HPV16 L2E7E6 fusion protein vaccine called Tissue Antigen &#8210; Cervical Intraepithelial Neoplasia and PD-1 blocker have synergistic effects in TC-1 tumors to better control tumors&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;14&#44;15</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Epigenetics has evolved into a hot topic in scientific research&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> N6-methyladenosine &#40;m<span class="elsevierStyleSup">6</span>A&#41; is a reversible methylation modification at the sixth N atom of adenine&#44;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a> which has been demonstrated to play an important role in many biological processes&#44; such as adipogenesis&#44; sperm germinal&#44; tumor&#44; and other diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#8211;20</span></a> However&#44; to date&#44; there have been few studies on how m<span class="elsevierStyleSup">6</span>A modifications affect the progression of cSCC&#46; Although m<span class="elsevierStyleSup">6</span>A has been the focus of many studies in recent years&#44; a comprehensive understanding of m<span class="elsevierStyleSup">6</span>A has yet to be realized&#44; and the underlying mechanisms of m<span class="elsevierStyleSup">6</span>A modification in cancer should be further investigated&#46; Recent studies have shown that m<span class="elsevierStyleSup">6</span>A modification is closely related to tumor immune microenvironment remodeling&#44; which may influence tumor development&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In this study&#44; the authors hypothesized that the use of HPV vaccination with anti-PD-1 injection could significantly increase the number of tumor-infiltrating CD8<span class="elsevierStyleSup">&#43;</span>T cells in mice with cSCC&#44; eliciting a significant immune response that would synergize with PD-1 blockade and would provide insights into the potential impact of HPV vaccination on currently understudied HPV-associated malignancies&#46; The idea that the HPV vaccine enhances the anti-PD-1 effect via METTL3 for the treatment of cSCC was also proposed through anthropological specimens&#44; cytological experiments&#44; and animal experiments&#46; The present findings reveal a previously unrecognized mechanism of mRNA methylation in cSCC sensitized to PD-1 blockade&#44; thus providing a potential therapeutic avenue for this malignant disease&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Tissue samples</span><p id="par0030" class="elsevierStylePara elsevierViewall">For the collection of cSCC samples from patients&#44; analyses were performed with the approval of the Ethical Committee of the First Hospital of Shanxi Medical University&#46; cSCC tissue was collected from 10 patients after surgery and the surgical details of those 10 patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; The pathologist confirmed the type of pathology in the sample&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Immunofluorescent staining</span><p id="par0035" class="elsevierStylePara elsevierViewall">Tumor sections embedded in paraffin were dried at 90&#8239;&#176;C for 4&#8239;h&#44; dewaxed in xylene&#44; and then rehydrated in graded ethanol solutions&#46; Cooled tissue sections were immersed in 0&#46;3&#37; hydrogen peroxide solution for 15&#8239;min to block endogenous peroxidase activity&#44; rinsed with PBS for 5&#8239;min&#44; and blocked with 3&#37; BSA solution at room temperature for 30&#8239;min&#46; After washing by PBS&#44; the sections were incubated with antibodies &#40;Abcam&#44; Cambridge&#44; MA&#44; USA&#41; for 1 hour in 1&#37; BSA blocking buffer&#44; followed by incubated for 1&#46;5 hours of secondary antibody conjugated with Alexa Fluro 549 &#40;Thermal Fischer&#41; and DAPI&#46; Fluorescence images were obtained using a Zeiss LSM510 confocal microscope&#44; equipped with a 63&#215; immersion objective&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Cell culture</span><p id="par0040" class="elsevierStylePara elsevierViewall">A431&#40;Human cSCC cell&#41; and SCC7 &#40;mouse SCC cell&#41; were obtained from the Cell Bank of Shanghai Institute of Cell Biology &#40;Shanghai&#44; China&#41;&#46; These cells were maintained in a DMEM &#40;Thermo Fisher Scientific&#44; Waltham&#44; MA&#44; USA&#41;&#44; which is supplemented with 10&#37; FBS and 1&#37; penicillin-streptomycin&#46; Cells were cultured in a humidified incubator at 37&#8239;&#176;C with 5&#37; CO<span class="elsevierStyleInf">2</span> &#40;Sanyo Osaka&#44; Japan&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Preparation of CD8<span class="elsevierStyleSup">&#43;</span>T cells</span><p id="par0045" class="elsevierStylePara elsevierViewall">Peripheral blood mononuclear cells from blood donors were isolated by using the Ficoll gradient method&#44; and CD8<span class="elsevierStyleSup">&#43;</span>T cells were isolated from 1&#46;25&#8239;&#215;&#8239;10<span class="elsevierStyleSup">7</span> PBMCs by using the Easy Sep Human CD8<span class="elsevierStyleSup">&#43;</span>T Cell Isolation Kit&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Real-time PCR</span><p id="par0050" class="elsevierStylePara elsevierViewall">Extraction of total RNA was performed using TRIzol reagent &#40;Invitrogen&#44; Carlsbad&#44; CA&#44; USA&#41; and reverse-transcribed using the cDNA Synthesis kit &#40;Takara&#44; Japan&#41;&#46; The quantity and density of the RNA were verified by a spectrophotometer&#46; QRT-PCR was performed using the SYBR Green Master MIX Kit &#40;Takara&#44; Japan&#41; according to the manufacturer&#8217;s instructions&#46; The assays were performed in triplicate and relative gene expression was determined by using the 2<span class="elsevierStyleSup">-&#916;&#916;Ct</span> method&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">METTL3 forward&#58; 5&#8217;- CATCCGTCTTGCCATCTCTAC-3&#8217;</p><p id="par0060" class="elsevierStylePara elsevierViewall">METTL3 reverse&#58; 5&#8217;- GACCTCGCTTTACCTCAATCA-3&#8217;</p><p id="par0065" class="elsevierStylePara elsevierViewall">METTL14 forward&#58; 5&#8217;- GCATCACTGCGAATGAGAAATG-3&#8217;</p><p id="par0070" class="elsevierStylePara elsevierViewall">METTL14 reverse&#58; 5&#8217;- CAGAACCGCACCAGAGAAATA-3&#8217;</p><p id="par0075" class="elsevierStylePara elsevierViewall">RMB15 forward&#58; 5&#8217;- GCCCAACTCAAGATCACTCA-3&#8217;</p><p id="par0080" class="elsevierStylePara elsevierViewall">RBM15 reverse&#58; 5&#8217;- AGCCAGGAGAATGGCATAAC-3&#8217;</p><p id="par0085" class="elsevierStylePara elsevierViewall">WTAP forward&#58; 5&#8217;- AATGGTAGACCCAGCAATCAA-3&#8217;</p><p id="par0090" class="elsevierStylePara elsevierViewall">WTAP reverse&#58; 5&#8217;- CGTAAACTTCCAGGCACTCA-3&#8217;</p><p id="par0095" class="elsevierStylePara elsevierViewall">VIRMA forward&#58; 5&#8217;- GAGGCGGATCCTTTGAGTTT-3&#8217;</p><p id="par0100" class="elsevierStylePara elsevierViewall">VIRMA reverse&#58; 5&#8217;- AACGACCTGAGAGAGGGATAG-3&#8217;</p><p id="par0105" class="elsevierStylePara elsevierViewall">FTO forward&#58; 5&#8217;- AGAGCGGGAAGCTAAGAAAC-3&#8217;</p><p id="par0110" class="elsevierStylePara elsevierViewall">FTO reverse&#58; 5&#8217;- GCCACTGCTGATAGAACTCAT-3&#8217;</p><p id="par0115" class="elsevierStylePara elsevierViewall">ALKBH5 forward&#58; 5&#8217;- GTGGGTATGCTGCTGATGAA-3&#8217;</p><p id="par0120" class="elsevierStylePara elsevierViewall">ALKBH5 reverse&#58; 5&#8217;- TCGCGGTGCATCTAATCTTG-3&#8217;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Western blot</span><p id="par0125" class="elsevierStylePara elsevierViewall">To extract total proteins&#44; cell lysates were obtained using RIPA buffer &#40;Beyotime&#44; Shanghai&#44; China&#41; supplemented with phosphatase and protease inhibitors &#40;Yeasen&#44; Shanghai&#44; China&#41;&#46; A total of 15&#8239;&#956;L protein was injected into a Bis-Tris SDS&#47;PAGE gel and transferred to PVDF membranes&#46; After blocking with 5&#37; BSA&#44; the membranes were incubated with primary antibody overnight at 4&#8239;&#176;C&#46; Membranes were then exposed to the secondary antibody for 60&#8239;min&#46; The strips were incubated with an ECL kit and analyzed with an imaging system&#46; Densitometric analysis was performed by using Adobe Photoshop CS6&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Cytolytic assay</span><p id="par0130" class="elsevierStylePara elsevierViewall">Purified CD8<span class="elsevierStyleSup">&#43;</span>T cells were obtained by negative selection&#46; SCC was added to purified CD8<span class="elsevierStyleSup">&#43;</span>T cells at a 1&#58;10-50 ratio and cultured in 48-well trays &#40;Costar 3548&#44; Cambridge&#44; MA&#41; in RPMI 1640&#46; IL-2 &#40;50 units&#47;mL&#44; Chiron&#44; Emeryville&#44; CA&#41; was added to each well beginning on day 1 and every 2 to 3 days thereafter&#46; SCC cells were harvested on day 7 and assayed for lytic activity in triplicate using CCK-8 assay&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Enzyme-linked immunosorbent assay</span><p id="par0135" class="elsevierStylePara elsevierViewall">Enzyme-linked immunosorbent assay &#40;ELISA&#41; to detect cytokines was performed with kits &#40;Boster Bio&#44; Wuhan&#44; China&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">CCK-8 assay</span><p id="par0140" class="elsevierStylePara elsevierViewall">A total of 10<span class="elsevierStyleSup">3</span> cells were inoculated into each well of 96-well plates&#46; At each time point &#40;24&#8239;h&#44; 48&#8239;h&#44; 72&#8239;h&#44; and 96&#8239;h&#41;&#44; 10&#8239;&#956;L CCK-8 solution &#40;Yeasen&#44; Shanghai&#44; China&#41; was added to the sextuplicate wells&#46; The wells were incubated for 3&#8239;h&#44; and the absorbance of each well was determined at 450&#8239;nm&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">In vivo assays</span><p id="par0145" class="elsevierStylePara elsevierViewall">All of the animal experiments were approved by the Animal Experimentation Ethics Committee of the first Hospital&#44; Shanxi Medical University&#46; Eight-week-old C57BL&#47;6 mice were maintained according to the guidelines of the 3Rs &#40;Replacement&#44; Reduction&#44; and Refinement&#41;&#46; A total of 1&#8239;&#215;&#8239;10<span class="elsevierStyleSup">7</span> SCC7 cells resuspended in 100&#8239;&#956;L of PBS were inoculated subcutaneously in the left flank of the mice&#46; When the tumor volume reaches 50&#8210;100&#8239;mm<span class="elsevierStyleSup">3</span>&#44; anti-PD-1 antibody &#40;200&#8239;&#956;g&#47;mouse&#41; or combined HPV vaccine &#40;0&#46;25&#8239;&#956;L&#47;mouse&#41; was injected&#46; After the tumor was detected&#44; tumor size was measured every 5 days by a vernier caliper and tumor volume was calculated as volume &#40;cm<span class="elsevierStyleSup">3</span>&#41;&#8239;&#61;&#8239;L&#8239;&#215;&#8239;W<span class="elsevierStyleSup">2</span>&#8239;&#215;&#8239;0&#46;5 with L and W representing the largest and smallest diameters&#44; respectively&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">m<span class="elsevierStyleSup">6</span>A RNA methylation quantification</span><p id="par0150" class="elsevierStylePara elsevierViewall">The m<span class="elsevierStyleSup">6</span>A RNA Methylation Assay Kit &#40;Abcam&#44; ab185912&#41; was used to evaluate the content of m<span class="elsevierStyleSup">6</span>A in total RNA&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Dot blot</span><p id="par0155" class="elsevierStylePara elsevierViewall">The poly&#40;A&#41; &#43; RNAs &#40;400&#8239;ng&#41; were double-diluted and spotted onto a nylon membrane &#40;GE Healthcare&#44; USA&#41;&#46; Briefly&#44; the membranes were then UV crosslinked&#44; blocked&#44; incubated with m<span class="elsevierStyleSup">6</span>A antibody and horseradish peroxidase-conjugated anti-rabbit IgG&#44; and finally detected with a 3&#44;3&#8217;-diaminobenzidine peroxidase substrate kit&#46; The same 400&#8239;ng poly&#40;A&#41;&#8239;&#43;&#8239;RNAs were spotted on the membrane&#44; stained with 0&#46;02&#37; Methylene blue in 0&#46;3&#8239;M sodium acetate for 2&#8239;h&#44; and washed with ribonuclease-free water for 5&#8239;h&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Statistical analysis</span><p id="par0160" class="elsevierStylePara elsevierViewall">Statistical analyses were performed using the SPSS software version 19&#46;0 &#40;SPSS&#44; Inc&#46;&#44; Chicago&#44; IL&#41; or GraphPad Prism 7&#46;0 &#40;GraphPad Software&#44; USA&#41; as previously described&#46; The values are presented as the mean&#8239;&#177;&#8239;Standard Deviation &#40;SD&#41;&#46; For comparisons&#44; Student&#8217;s <span class="elsevierStyleItalic">t</span>-test and one-way ANOVA test by Least Significant Difference test were performed&#44; as appropriate&#59; p&#8239;&#60;&#8239;0&#46;05 was considered statistically significant&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Results</span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">HPV vaccination enhances the infiltration of immune cells in human cSCC tissues</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors selected five cases each of HPV-vaccinated and non-HPV-vaccinated cSCC patients&#39; tumor tissues in order to determine the effect of the HPV vaccine on immune cells in human cSCC tissues&#44; and analyzed the infiltration of CD8&#44; CD4&#44; NK&#44; DC&#44; and Macrophages in cSCC tumors by immunofluorescence&#46; There was a statistical significant difference between the two groups in the five types of immune cells&#46; The expression of CD8&#44; CD4&#44; CD69&#44; CD11c&#44; and CD163 in the tumors of humans in the vaccinated group was significantly increased &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#8210;B&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">HPV vaccine enhances the killing ability of CD8<span class="elsevierStyleSup">&#43;</span>T cells</span><p id="par0170" class="elsevierStylePara elsevierViewall">To investigate the effect of the HPV vaccine on CD8<span class="elsevierStyleSup">&#43;</span>T cell activity&#44; the authors co-cultured CD8<span class="elsevierStyleSup">&#43;</span>T cells with A431 cells at 10&#58;1&#44; 25&#58;1 and 50&#58;1 ratios and added 2&#8239;&#956;g or 10&#8239;&#956;g of bivalent HPV vaccine Cervarix &#40;GSK&#44; 0&#46;5&#8239;&#956;g&#47;mL&#41;&#46; CD8<span class="elsevierStyleSup">&#43;</span>T cells showed higher cytotoxic activity after adding the HPV vaccine&#44; however&#44; the differences in the killing activity of the HPV vaccine at different concentrations on A431 cells were not statistically significant at a certain potency-target ratio &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#46; To explore the effect of HPV vaccine on cytokine secretion in the co-culture system&#44; the authors examined IFN-&#947;&#44; TNF-&#945;&#44; TGF-&#946;&#44; IL-17&#44; IL-12&#44; and IL-33 in the supernatant&#44; and the secretion of IFN-&#947;&#44; TNF-&#945;&#44; TGF-&#946;&#44; and IL-17 increased significantly after the addition of 2&#8239;&#956;g of HPV vaccine&#44; while the secretion increased after the addition of 10&#8239;&#956;g of HPV vaccine was IFN-&#947;&#44; TNF-&#945;&#44; TGF-&#946;&#44; and IL-33 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">HPV vaccine combined with anti-PD1 monoclonal antibody treatment inhibits tumor development in mice in vivo</span><p id="par0175" class="elsevierStylePara elsevierViewall">To further analyze the effect of the HPV vaccine on cSCC at the animal level&#44; the authors hypothesized that the addition of the HPV vaccine would enhance the immunogenicity and antitumor effects of PD-1 treatment in mice&#46; To test this hypothesis&#44; the authors divided 10 mice with cSCC into two groups of 5 mice each and injected PD-1 Abs &#40;10377-M94&#44; SinoBiological&#41; or PD-1Abs&#43;HPV vaccine&#46; The authors did not set up a no-treatment group reflecting the therapeutic effect of PD-1 on cSCC&#44; because it has been concluded that PD-1 monoclonal antibody has a significant inhibitory effect on cSCC in other studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;25</span></a> To monitor the antitumor response&#44; tumor volume was measured every 5 days&#44; and mice were executed at day 30&#44; tumor tissue was isolated and weight was measured &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A&#41;&#46; Compared to PD-1 Abs&#44; tumors in the PD-1Abs&#43;HPV vaccine group were reduced in weight &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>B&#41; and volume &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>C&#41; at day 30&#44; which demonstrated that stable regression was observed on tumors in all groups&#46; Immunofluorescence analysis of mouse tumor tissues observed a significant increase in intratumoral infiltration of CD8&#44; CD4&#44; NK&#44; DC&#44; and Macrophage in PD-1 monoclonal antibody combined with HPV vaccine mice &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#8210;B&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0180" class="elsevierStylePara elsevierViewall">With the purpose of observing the effect of the HPV vaccine on m<span class="elsevierStyleSup">6</span>A in tumor tissues&#44; the authors analyzed the m<span class="elsevierStyleSup">6</span>A content in mouse tumor tissues using a colorimetric method and Dot blot and found that the m<span class="elsevierStyleSup">6</span>A content in the PD-1Abs&#43;HPV vaccine group was significantly lower than that in the PD-1 Abs group &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>A&#8210;B&#41;&#46; The authors further screened the expression of m<span class="elsevierStyleSup">6</span>A methylesterase and demethylase by qPCR&#44; and the results were shown in 3H&#46; METTL3 was significantly downregulated in the presence of HPV vaccine&#44; while the differences of METTL14&#44; RBM15&#44; WTAP&#44; VIRMA&#44; FTO&#44; and ALKBH5 were not statistically significant &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>A&#41;&#46; The downregulation of METTL3 expression at the protein level in PD-1Abs&#43;HPV vaccine group was further verified by Western blot &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>B&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">METTL3-mediated HPV vaccine enhances susceptibility to cSCC immunotherapy</span><p id="par0185" class="elsevierStylePara elsevierViewall">To further study the effect of the HPV vaccine on METTL3 expression in cSCC&#44; the authors overexpressed METTL3&#44; qPCR and Western blot were performed to detect the overexpression efficiency at mRNA and protein levels &#40;<a class="elsevierStyleCrossRef" href="#fig0035">Fig&#46; 7</a>A&#8210;B&#41;&#46; CCK-8 assay revealed that there was no significant difference in cell activity between the six groups within 24 hours of incubation&#46; After 96 hours of culture&#44; cell activity was significantly reduced when co-cultured with CD8<span class="elsevierStyleSup">&#43;</span>T cells and A431 cells compared with the control group&#44; and further reduced in A431 cell activity after the addition of HPV vaccine&#44; with statistical differences between all groups&#46; After overexpression of METTL3&#44; it still showed the inhibitory effect of CD8<span class="elsevierStyleSup">&#43;</span>T cells and HPV vaccine on A431 cell activity&#44; and A431 cell activity was significantly higher in the CD8<span class="elsevierStyleSup">&#43;</span>T cells&#43;HPV vaccine-OE-METTL3 group than in the CD8<span class="elsevierStyleSup">&#43;</span>T cells&#43;HPV vaccine-OE-NC group &#40;<a class="elsevierStyleCrossRef" href="#fig0040">Fig&#46; 8</a>A&#41;&#46; Also&#44; the authors examined m<span class="elsevierStyleSup">6</span>A in each group and found that HPV vaccine significantly reduced the total m<span class="elsevierStyleSup">6</span>A content in the co-culture system&#44; while METTL3 overexpression significantly abolished this effect&#46; Interestingly&#44; the m<span class="elsevierStyleSup">6</span>A content in the CD8<span class="elsevierStyleSup">&#43;</span>T cells&#43;HPV vaccine-OE-NC group was not statistically significantly different from Control -OE-NC&#44; while the m<span class="elsevierStyleSup">6</span>A content in the CD8<span class="elsevierStyleSup">&#43;</span>T cells -OE-NC group was elevated compared to Control -OE-NC&#44; although there was no statistical difference &#40;<a class="elsevierStyleCrossRef" href="#fig0040">Fig&#46; 8</a>B&#41;&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia><elsevierMultimedia ident="fig0040"></elsevierMultimedia></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Overexpression of METTL3 abolishes HPV vaccine inhibition of cSCC in vivo</span><p id="par0190" class="elsevierStylePara elsevierViewall">For further evaluation of METTL3 in the HPV vaccine against csCC&#44; xenograft tumor experiments were performed&#46; The authors divided the mouse models of cSCC into 4 groups of 5 mice each and gave PD-1 Abs&#43;OE-NC&#44; PD-1 Abs&#43;HPV vaccine&#43;OE-NC&#44; PD-1 Abs&#43;OE-METTL3&#44; and PD-1 Abs&#43;HPV vaccine&#43;OE-METTL3 treatments respectively&#46; In the combination of anti-PD-1 antibody and HPV vaccine&#44; tumor volume and weight were significantly reduced&#44; and co-treatment with HPV vaccination and anti-mouse PD-1 antibody resulted in complete inhibition of tumor growth&#44; while the inhibitory effect of anti-PD-1 antibody on tumor volume and weight was attenuated after overexpression of mettl3 &#40;<a class="elsevierStyleCrossRef" href="#fig0045">Fig&#46; 9</a>A&#8210;C&#41;&#46; Histologically&#44; it was found that the PD-1 Abs&#43;HPV vaccine&#43;OE-NC group had significantly more intratumoral infiltrates of CD8&#44; CD4&#44; NK&#44; DC&#44; and Macrophages than the other groups &#40;<a class="elsevierStyleCrossRef" href="#fig0050">Fig&#46; 10</a>A&#8210;B&#41;&#46;</p><elsevierMultimedia ident="fig0045"></elsevierMultimedia><elsevierMultimedia ident="fig0050"></elsevierMultimedia></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Discussion</span><p id="par0195" class="elsevierStylePara elsevierViewall">Immunosuppression is mainly manifested by diminished or absent proliferative capacity of T lymphocytes and dysfunctional cytokine secretion&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> CD8<span class="elsevierStyleSup">&#43;</span>T cells are immune cells that can recognize and kill cancer cells&#44; considered to have tumor-eradication potential&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> The present study found that the HPV vaccine enhanced the toxic effects of CD8<span class="elsevierStyleSup">&#43;</span>T cells on cSCC&#46; CD8<span class="elsevierStyleSup">&#43;</span>T cells are multiple cytokine producers and the HPV vaccine resulted in increased secretion of IFN-&#947;&#44; TNF-&#945;&#44; TGF-&#946;&#44; IL-17&#44; IL-33 by CD8<span class="elsevierStyleSup">&#43;</span>T cells&#46; Yunyan Sun concluded that both cervicovaginal vaccinations with TA-HPV could induce a strong local HPV-16E7 antigen-specific CD8<span class="elsevierStyleSup">&#43;</span>T cell immune response&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The present results suggest that after HPV vaccination in humans&#44; the body produces a certain amount of specific T-cell immune response along with antigen-antibody response&#44; and the resulting cytokines play a role in suppressing cutaneous squamous carcinoma cells&#44; suggesting that HPV vaccine may be better at stimulating antitumor immune response&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">RNA modifying enzymes are crucial for tumor survival in the process of immunotherapy&#44; and m<span class="elsevierStyleSup">6</span>A modifications play oncogenic roles in many cancers&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> The present results showed that overexpression of METTL3 in cSCC cells increased the level of m<span class="elsevierStyleSup">6</span>A modification in cSCC cells&#44; which confirmed the study of Renpeng Zhou from the side&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> indicating that METTL3 maintained m<span class="elsevierStyleSup">6</span>A modification in tumor cells and promoted the proliferative activity of cancer cells in cSCC&#46; Therefore&#44; the authors conclude that the HPV vaccine inhibits the development of squamous carcinoma by down-regulating METTL3&#44; probably because the downregulation of METTL3 expression increases the sensitivity of tumor cells to cytokines&#46; Lingling Wang suggested that high METTL3 expression status was negatively correlated with tumor immune cell infiltration&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> likewise&#44; the results showed that the immune infiltrating cells in cSCC tissues were significantly reduced after METTL3 overexpression in the animal experiment of this study&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">METTL3 may be a potential target for clinical treatment of cSCC&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Eliza Yankova demonstrated that a METTL3 inhibitor &#40;STM2457&#41; inhibits the carcinogenic effects caused by METTL3 enzyme overexpression in both in vitro cellular and in vivo animal experiments&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> lingling Wang demonstrated that depletion of the methyltransferases Mettl3 and Mettl14 enhanced response to anti-PD-1 treatment in colorectal cancer and melanoma&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Overexpression of METTL3 followed by treatment with PD-1 monoclonal antibodies did not show a significant trend of tumor regression in the present results&#44; whereas the HPV vaccine has the potential to act as a METTL3 inhibitor&#44; and the combination with PD-1 monoclonal antibodies for cSCC played a synergistic role to further slowdown the tumor growth&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">There is an urgent need to discover precise and effective targets for current therapeutic approaches in cSCC&#46; The main finding of this study was that HPV vaccine treatment of squamous carcinoma is correlated with METTL3 expression and also inhibited the formation of an immunosuppressive tumor microenvironment&#46; There are certain shortcomings in this study&#44; the sample size of clinical samples is small&#44; and sufficient samples may need to be collected for future studies&#44; while further use of m<span class="elsevierStyleSup">6</span>A sequencing and transcriptome sequencing may be needed to deeply explore the molecular regulatory mechanisms of METTL3-mediated HPV vaccine treatment for cSCC&#46; In conclusion&#44; the present experiments suggest that METTL3 is a promising target for the treatment of cSCC that can be downregulated by HPV vaccines&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conclusions</span><p id="par0215" class="elsevierStylePara elsevierViewall">The HPV vaccine enhances the sensitivity of anti-PD-1 treatment by down-regulating METTL3 in cutaneous squamous cell carcinoma&#46; The combination of HPV vaccine and PD-1 monoclonal antibody treatment produces an immune infiltration-enhancing effect&#44; resulting in better tumor control and promoting tumor clearance&#46; Overall&#44; this study provides some reference value for the in-depth exploration and research of the HPV vaccine&#46; In future studies&#44; research on the mechanistic aspects of METTL3 should be further strengthened&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Financial support</span><p id="par0220" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Authors&#8217; contributions</span><p id="par0225" class="elsevierStylePara elsevierViewall">Yingjie Zhang&#58; The study concept and design&#59; data collection&#44; or analysis and interpretation of data&#59; writing of the manuscript&#59; data collection&#44; analysis and interpretation&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Yiru Wang&#58; Data collection&#44; or analysis and interpretation of data&#59; data collection&#44; analysis&#44; and interpretation&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Shuping Guo&#58; Statistical analysis&#59; data collection&#44; analysis&#44; and interpretation&#59; effective participation in the research guidance&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Hongzhou Cui&#58; Critical review of important intellectual content&#59; effective participation in the research guidance&#59; critical review of the literature&#59; final approval of the final version of the manuscript&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conflicts of interest</span><p id="par0245" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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              "titulo" => "HPV vaccination enhances the infiltration of immune cells in human cSCC tissues"
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              "titulo" => "HPV vaccine enhances the killing ability of CD8T cells"
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              "titulo" => "METTL3-mediated HPV vaccine enhances susceptibility to cSCC immunotherapy"
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              "titulo" => "Overexpression of METTL3 abolishes HPV vaccine inhibition of cSCC in vivo"
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    "fechaRecibido" => "2023-03-16"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Cutaneous squamous cell carcinoma &#40;cSCC&#41; develops from epithelial keratinocytes by dysregulation of self-renewal and differentiation&#46; Recent studies have found that the size and number of cSCC tumors gradually decrease or even disappear after HPV vaccination&#46; However&#44; the role of the HPV vaccine in the cSCC mechanism is poorly understood&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">The aim of this study is to investigate the effect and mechanism of the HPV vaccine in cSCC&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Immunofluorescence was used to study the immune infiltrating cells in the tumor tissues of patients with cSCC&#46; The effects of the HPV vaccine on cSCC cells and tissues were studied by Cell Culture&#44; Real-time PCR&#44; Western Blot&#44; Cytotoxicity Assay&#44; Enzyme-linked Immunosorbent Assay&#44; m6A Blotting&#44; CCK-8 Assay&#44; m6A Ribonucleic acid Methylation Quantification and tumor transplantation&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">The HPV vaccine enhanced the toxic effect of CD8<span class="elsevierStyleSup">&#43;</span>T cells on cSCC cells and promoted the secretion of multiple cytokines by CD8<span class="elsevierStyleSup">&#43;</span>T cells&#46; In addition&#44; HPV vaccines can increase tumor sensitivity to anti-PD-1 therapy by downregulating METTL3 in tumor tissue&#44; with the combination of HPV vaccine and PD-1 monoclonal antibodies producing enhanced immune cell infiltration compared to PD-1 blockade alone&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Study limitations</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">It is important to note the limitations of this study&#44; including the small sample size&#44; the construction of the mouse model&#44; and the choice of HPV vaccine and PD-1 monoclonal antibody&#44; which may limit the generalization of our findings to a wider population&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclusions</span><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">It is hoped that this research will contribute to a deeper understanding of the role of the HPV vaccine in the treatment of cSCC&#46; HPV vaccine is expected to become an important approach to alleviate the development of cSCC&#46;</p></span>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Animal-level validation of METTL3 overexpression abolishing HPV vaccine to enhance the sensitivity of cSCC mice treated with PD-1 monoclonal antibody&#46; &#40;A&#41; Tumor picture&#59; &#40;B&#41; volume change&#59; &#40;C&#41; weight change&#46; &#42;&#42;&#42;p&#8239;&#60;&#8239;0&#46;001&#46;</p>"
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          0 => array:4 [
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          0 => array:3 [
            "identificador" => "at0050"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Effect of overexpression of METTL3 on combination therapy in immunofluorescence&#46; &#40;A&#41; Immunofluorescence observation of immune microenvironment differences &#40;CD8&#44; CD4&#44; NK&#44; DC&#44; Macrophage&#41;&#59; &#40;B&#41; Image J statistical analysis of immune cell positive ratio&#46; &#42;&#42;&#42;p&#8239;&#60;&#8239;0&#46;001&#46;</p>"
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HPV vaccination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Site&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diameter&#40;cm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Procedure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anogenital areas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mohs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neck&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vermillion lips&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mohs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pretibial areas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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Original Article
METTL3-mediated HPV vaccine enhances the effect of anti PD-1 immunotherapy to alleviate the development of cutaneous squamous cell carcinoma
Yingjie Zhanga,b, Yiru Wangc, Shuping Guoa, Hongzhou Cuia,b,
Corresponding author
menjuncui@163.com

Corresponding author.
a Department of Dermatology, First Hospital of Shanxi Medical University, Taiyuan, China
b The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
c Department of Dermatology, Taiyuan Maternity and Child Health Care Hospital, Taiyuan, China
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It has been reported that the HPV16 L2E7E6 fusion protein vaccine called Tissue Antigen &#8210; Cervical Intraepithelial Neoplasia and PD-1 blocker have synergistic effects in TC-1 tumors to better control tumors&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;14&#44;15</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Epigenetics has evolved into a hot topic in scientific research&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> N6-methyladenosine &#40;m<span class="elsevierStyleSup">6</span>A&#41; is a reversible methylation modification at the sixth N atom of adenine&#44;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a> which has been demonstrated to play an important role in many biological processes&#44; such as adipogenesis&#44; sperm germinal&#44; tumor&#44; and other diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#8211;20</span></a> However&#44; to date&#44; there have been few studies on how m<span class="elsevierStyleSup">6</span>A modifications affect the progression of cSCC&#46; Although m<span class="elsevierStyleSup">6</span>A has been the focus of many studies in recent years&#44; a comprehensive understanding of m<span class="elsevierStyleSup">6</span>A has yet to be realized&#44; and the underlying mechanisms of m<span class="elsevierStyleSup">6</span>A modification in cancer should be further investigated&#46; Recent studies have shown that m<span class="elsevierStyleSup">6</span>A modification is closely related to tumor immune microenvironment remodeling&#44; which may influence tumor development&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In this study&#44; the authors hypothesized that the use of HPV vaccination with anti-PD-1 injection could significantly increase the number of tumor-infiltrating CD8<span class="elsevierStyleSup">&#43;</span>T cells in mice with cSCC&#44; eliciting a significant immune response that would synergize with PD-1 blockade and would provide insights into the potential impact of HPV vaccination on currently understudied HPV-associated malignancies&#46; The idea that the HPV vaccine enhances the anti-PD-1 effect via METTL3 for the treatment of cSCC was also proposed through anthropological specimens&#44; cytological experiments&#44; and animal experiments&#46; The present findings reveal a previously unrecognized mechanism of mRNA methylation in cSCC sensitized to PD-1 blockade&#44; thus providing a potential therapeutic avenue for this malignant disease&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Tissue samples</span><p id="par0030" class="elsevierStylePara elsevierViewall">For the collection of cSCC samples from patients&#44; analyses were performed with the approval of the Ethical Committee of the First Hospital of Shanxi Medical University&#46; cSCC tissue was collected from 10 patients after surgery and the surgical details of those 10 patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; The pathologist confirmed the type of pathology in the sample&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Immunofluorescent staining</span><p id="par0035" class="elsevierStylePara elsevierViewall">Tumor sections embedded in paraffin were dried at 90&#8239;&#176;C for 4&#8239;h&#44; dewaxed in xylene&#44; and then rehydrated in graded ethanol solutions&#46; Cooled tissue sections were immersed in 0&#46;3&#37; hydrogen peroxide solution for 15&#8239;min to block endogenous peroxidase activity&#44; rinsed with PBS for 5&#8239;min&#44; and blocked with 3&#37; BSA solution at room temperature for 30&#8239;min&#46; After washing by PBS&#44; the sections were incubated with antibodies &#40;Abcam&#44; Cambridge&#44; MA&#44; USA&#41; for 1 hour in 1&#37; BSA blocking buffer&#44; followed by incubated for 1&#46;5 hours of secondary antibody conjugated with Alexa Fluro 549 &#40;Thermal Fischer&#41; and DAPI&#46; Fluorescence images were obtained using a Zeiss LSM510 confocal microscope&#44; equipped with a 63&#215; immersion objective&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Cell culture</span><p id="par0040" class="elsevierStylePara elsevierViewall">A431&#40;Human cSCC cell&#41; and SCC7 &#40;mouse SCC cell&#41; were obtained from the Cell Bank of Shanghai Institute of Cell Biology &#40;Shanghai&#44; China&#41;&#46; These cells were maintained in a DMEM &#40;Thermo Fisher Scientific&#44; Waltham&#44; MA&#44; USA&#41;&#44; which is supplemented with 10&#37; FBS and 1&#37; penicillin-streptomycin&#46; Cells were cultured in a humidified incubator at 37&#8239;&#176;C with 5&#37; CO<span class="elsevierStyleInf">2</span> &#40;Sanyo Osaka&#44; Japan&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Preparation of CD8<span class="elsevierStyleSup">&#43;</span>T cells</span><p id="par0045" class="elsevierStylePara elsevierViewall">Peripheral blood mononuclear cells from blood donors were isolated by using the Ficoll gradient method&#44; and CD8<span class="elsevierStyleSup">&#43;</span>T cells were isolated from 1&#46;25&#8239;&#215;&#8239;10<span class="elsevierStyleSup">7</span> PBMCs by using the Easy Sep Human CD8<span class="elsevierStyleSup">&#43;</span>T Cell Isolation Kit&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Real-time PCR</span><p id="par0050" class="elsevierStylePara elsevierViewall">Extraction of total RNA was performed using TRIzol reagent &#40;Invitrogen&#44; Carlsbad&#44; CA&#44; USA&#41; and reverse-transcribed using the cDNA Synthesis kit &#40;Takara&#44; Japan&#41;&#46; The quantity and density of the RNA were verified by a spectrophotometer&#46; QRT-PCR was performed using the SYBR Green Master MIX Kit &#40;Takara&#44; Japan&#41; according to the manufacturer&#8217;s instructions&#46; The assays were performed in triplicate and relative gene expression was determined by using the 2<span class="elsevierStyleSup">-&#916;&#916;Ct</span> method&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">METTL3 forward&#58; 5&#8217;- CATCCGTCTTGCCATCTCTAC-3&#8217;</p><p id="par0060" class="elsevierStylePara elsevierViewall">METTL3 reverse&#58; 5&#8217;- GACCTCGCTTTACCTCAATCA-3&#8217;</p><p id="par0065" class="elsevierStylePara elsevierViewall">METTL14 forward&#58; 5&#8217;- GCATCACTGCGAATGAGAAATG-3&#8217;</p><p id="par0070" class="elsevierStylePara elsevierViewall">METTL14 reverse&#58; 5&#8217;- CAGAACCGCACCAGAGAAATA-3&#8217;</p><p id="par0075" class="elsevierStylePara elsevierViewall">RMB15 forward&#58; 5&#8217;- GCCCAACTCAAGATCACTCA-3&#8217;</p><p id="par0080" class="elsevierStylePara elsevierViewall">RBM15 reverse&#58; 5&#8217;- AGCCAGGAGAATGGCATAAC-3&#8217;</p><p id="par0085" class="elsevierStylePara elsevierViewall">WTAP forward&#58; 5&#8217;- AATGGTAGACCCAGCAATCAA-3&#8217;</p><p id="par0090" class="elsevierStylePara elsevierViewall">WTAP reverse&#58; 5&#8217;- CGTAAACTTCCAGGCACTCA-3&#8217;</p><p id="par0095" class="elsevierStylePara elsevierViewall">VIRMA forward&#58; 5&#8217;- GAGGCGGATCCTTTGAGTTT-3&#8217;</p><p id="par0100" class="elsevierStylePara elsevierViewall">VIRMA reverse&#58; 5&#8217;- AACGACCTGAGAGAGGGATAG-3&#8217;</p><p id="par0105" class="elsevierStylePara elsevierViewall">FTO forward&#58; 5&#8217;- AGAGCGGGAAGCTAAGAAAC-3&#8217;</p><p id="par0110" class="elsevierStylePara elsevierViewall">FTO reverse&#58; 5&#8217;- GCCACTGCTGATAGAACTCAT-3&#8217;</p><p id="par0115" class="elsevierStylePara elsevierViewall">ALKBH5 forward&#58; 5&#8217;- GTGGGTATGCTGCTGATGAA-3&#8217;</p><p id="par0120" class="elsevierStylePara elsevierViewall">ALKBH5 reverse&#58; 5&#8217;- TCGCGGTGCATCTAATCTTG-3&#8217;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Western blot</span><p id="par0125" class="elsevierStylePara elsevierViewall">To extract total proteins&#44; cell lysates were obtained using RIPA buffer &#40;Beyotime&#44; Shanghai&#44; China&#41; supplemented with phosphatase and protease inhibitors &#40;Yeasen&#44; Shanghai&#44; China&#41;&#46; A total of 15&#8239;&#956;L protein was injected into a Bis-Tris SDS&#47;PAGE gel and transferred to PVDF membranes&#46; After blocking with 5&#37; BSA&#44; the membranes were incubated with primary antibody overnight at 4&#8239;&#176;C&#46; Membranes were then exposed to the secondary antibody for 60&#8239;min&#46; The strips were incubated with an ECL kit and analyzed with an imaging system&#46; Densitometric analysis was performed by using Adobe Photoshop CS6&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Cytolytic assay</span><p id="par0130" class="elsevierStylePara elsevierViewall">Purified CD8<span class="elsevierStyleSup">&#43;</span>T cells were obtained by negative selection&#46; SCC was added to purified CD8<span class="elsevierStyleSup">&#43;</span>T cells at a 1&#58;10-50 ratio and cultured in 48-well trays &#40;Costar 3548&#44; Cambridge&#44; MA&#41; in RPMI 1640&#46; IL-2 &#40;50 units&#47;mL&#44; Chiron&#44; Emeryville&#44; CA&#41; was added to each well beginning on day 1 and every 2 to 3 days thereafter&#46; SCC cells were harvested on day 7 and assayed for lytic activity in triplicate using CCK-8 assay&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Enzyme-linked immunosorbent assay</span><p id="par0135" class="elsevierStylePara elsevierViewall">Enzyme-linked immunosorbent assay &#40;ELISA&#41; to detect cytokines was performed with kits &#40;Boster Bio&#44; Wuhan&#44; China&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">CCK-8 assay</span><p id="par0140" class="elsevierStylePara elsevierViewall">A total of 10<span class="elsevierStyleSup">3</span> cells were inoculated into each well of 96-well plates&#46; At each time point &#40;24&#8239;h&#44; 48&#8239;h&#44; 72&#8239;h&#44; and 96&#8239;h&#41;&#44; 10&#8239;&#956;L CCK-8 solution &#40;Yeasen&#44; Shanghai&#44; China&#41; was added to the sextuplicate wells&#46; The wells were incubated for 3&#8239;h&#44; and the absorbance of each well was determined at 450&#8239;nm&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">In vivo assays</span><p id="par0145" class="elsevierStylePara elsevierViewall">All of the animal experiments were approved by the Animal Experimentation Ethics Committee of the first Hospital&#44; Shanxi Medical University&#46; Eight-week-old C57BL&#47;6 mice were maintained according to the guidelines of the 3Rs &#40;Replacement&#44; Reduction&#44; and Refinement&#41;&#46; A total of 1&#8239;&#215;&#8239;10<span class="elsevierStyleSup">7</span> SCC7 cells resuspended in 100&#8239;&#956;L of PBS were inoculated subcutaneously in the left flank of the mice&#46; When the tumor volume reaches 50&#8210;100&#8239;mm<span class="elsevierStyleSup">3</span>&#44; anti-PD-1 antibody &#40;200&#8239;&#956;g&#47;mouse&#41; or combined HPV vaccine &#40;0&#46;25&#8239;&#956;L&#47;mouse&#41; was injected&#46; After the tumor was detected&#44; tumor size was measured every 5 days by a vernier caliper and tumor volume was calculated as volume &#40;cm<span class="elsevierStyleSup">3</span>&#41;&#8239;&#61;&#8239;L&#8239;&#215;&#8239;W<span class="elsevierStyleSup">2</span>&#8239;&#215;&#8239;0&#46;5 with L and W representing the largest and smallest diameters&#44; respectively&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">m<span class="elsevierStyleSup">6</span>A RNA methylation quantification</span><p id="par0150" class="elsevierStylePara elsevierViewall">The m<span class="elsevierStyleSup">6</span>A RNA Methylation Assay Kit &#40;Abcam&#44; ab185912&#41; was used to evaluate the content of m<span class="elsevierStyleSup">6</span>A in total RNA&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Dot blot</span><p id="par0155" class="elsevierStylePara elsevierViewall">The poly&#40;A&#41; &#43; RNAs &#40;400&#8239;ng&#41; were double-diluted and spotted onto a nylon membrane &#40;GE Healthcare&#44; USA&#41;&#46; Briefly&#44; the membranes were then UV crosslinked&#44; blocked&#44; incubated with m<span class="elsevierStyleSup">6</span>A antibody and horseradish peroxidase-conjugated anti-rabbit IgG&#44; and finally detected with a 3&#44;3&#8217;-diaminobenzidine peroxidase substrate kit&#46; The same 400&#8239;ng poly&#40;A&#41;&#8239;&#43;&#8239;RNAs were spotted on the membrane&#44; stained with 0&#46;02&#37; Methylene blue in 0&#46;3&#8239;M sodium acetate for 2&#8239;h&#44; and washed with ribonuclease-free water for 5&#8239;h&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Statistical analysis</span><p id="par0160" class="elsevierStylePara elsevierViewall">Statistical analyses were performed using the SPSS software version 19&#46;0 &#40;SPSS&#44; Inc&#46;&#44; Chicago&#44; IL&#41; or GraphPad Prism 7&#46;0 &#40;GraphPad Software&#44; USA&#41; as previously described&#46; The values are presented as the mean&#8239;&#177;&#8239;Standard Deviation &#40;SD&#41;&#46; For comparisons&#44; Student&#8217;s <span class="elsevierStyleItalic">t</span>-test and one-way ANOVA test by Least Significant Difference test were performed&#44; as appropriate&#59; p&#8239;&#60;&#8239;0&#46;05 was considered statistically significant&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Results</span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">HPV vaccination enhances the infiltration of immune cells in human cSCC tissues</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors selected five cases each of HPV-vaccinated and non-HPV-vaccinated cSCC patients&#39; tumor tissues in order to determine the effect of the HPV vaccine on immune cells in human cSCC tissues&#44; and analyzed the infiltration of CD8&#44; CD4&#44; NK&#44; DC&#44; and Macrophages in cSCC tumors by immunofluorescence&#46; There was a statistical significant difference between the two groups in the five types of immune cells&#46; The expression of CD8&#44; CD4&#44; CD69&#44; CD11c&#44; and CD163 in the tumors of humans in the vaccinated group was significantly increased &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#8210;B&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">HPV vaccine enhances the killing ability of CD8<span class="elsevierStyleSup">&#43;</span>T cells</span><p id="par0170" class="elsevierStylePara elsevierViewall">To investigate the effect of the HPV vaccine on CD8<span class="elsevierStyleSup">&#43;</span>T cell activity&#44; the authors co-cultured CD8<span class="elsevierStyleSup">&#43;</span>T cells with A431 cells at 10&#58;1&#44; 25&#58;1 and 50&#58;1 ratios and added 2&#8239;&#956;g or 10&#8239;&#956;g of bivalent HPV vaccine Cervarix &#40;GSK&#44; 0&#46;5&#8239;&#956;g&#47;mL&#41;&#46; CD8<span class="elsevierStyleSup">&#43;</span>T cells showed higher cytotoxic activity after adding the HPV vaccine&#44; however&#44; the differences in the killing activity of the HPV vaccine at different concentrations on A431 cells were not statistically significant at a certain potency-target ratio &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#46; To explore the effect of HPV vaccine on cytokine secretion in the co-culture system&#44; the authors examined IFN-&#947;&#44; TNF-&#945;&#44; TGF-&#946;&#44; IL-17&#44; IL-12&#44; and IL-33 in the supernatant&#44; and the secretion of IFN-&#947;&#44; TNF-&#945;&#44; TGF-&#946;&#44; and IL-17 increased significantly after the addition of 2&#8239;&#956;g of HPV vaccine&#44; while the secretion increased after the addition of 10&#8239;&#956;g of HPV vaccine was IFN-&#947;&#44; TNF-&#945;&#44; TGF-&#946;&#44; and IL-33 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">HPV vaccine combined with anti-PD1 monoclonal antibody treatment inhibits tumor development in mice in vivo</span><p id="par0175" class="elsevierStylePara elsevierViewall">To further analyze the effect of the HPV vaccine on cSCC at the animal level&#44; the authors hypothesized that the addition of the HPV vaccine would enhance the immunogenicity and antitumor effects of PD-1 treatment in mice&#46; To test this hypothesis&#44; the authors divided 10 mice with cSCC into two groups of 5 mice each and injected PD-1 Abs &#40;10377-M94&#44; SinoBiological&#41; or PD-1Abs&#43;HPV vaccine&#46; The authors did not set up a no-treatment group reflecting the therapeutic effect of PD-1 on cSCC&#44; because it has been concluded that PD-1 monoclonal antibody has a significant inhibitory effect on cSCC in other studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;25</span></a> To monitor the antitumor response&#44; tumor volume was measured every 5 days&#44; and mice were executed at day 30&#44; tumor tissue was isolated and weight was measured &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A&#41;&#46; Compared to PD-1 Abs&#44; tumors in the PD-1Abs&#43;HPV vaccine group were reduced in weight &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>B&#41; and volume &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>C&#41; at day 30&#44; which demonstrated that stable regression was observed on tumors in all groups&#46; Immunofluorescence analysis of mouse tumor tissues observed a significant increase in intratumoral infiltration of CD8&#44; CD4&#44; NK&#44; DC&#44; and Macrophage in PD-1 monoclonal antibody combined with HPV vaccine mice &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#8210;B&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0180" class="elsevierStylePara elsevierViewall">With the purpose of observing the effect of the HPV vaccine on m<span class="elsevierStyleSup">6</span>A in tumor tissues&#44; the authors analyzed the m<span class="elsevierStyleSup">6</span>A content in mouse tumor tissues using a colorimetric method and Dot blot and found that the m<span class="elsevierStyleSup">6</span>A content in the PD-1Abs&#43;HPV vaccine group was significantly lower than that in the PD-1 Abs group &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>A&#8210;B&#41;&#46; The authors further screened the expression of m<span class="elsevierStyleSup">6</span>A methylesterase and demethylase by qPCR&#44; and the results were shown in 3H&#46; METTL3 was significantly downregulated in the presence of HPV vaccine&#44; while the differences of METTL14&#44; RBM15&#44; WTAP&#44; VIRMA&#44; FTO&#44; and ALKBH5 were not statistically significant &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>A&#41;&#46; The downregulation of METTL3 expression at the protein level in PD-1Abs&#43;HPV vaccine group was further verified by Western blot &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>B&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">METTL3-mediated HPV vaccine enhances susceptibility to cSCC immunotherapy</span><p id="par0185" class="elsevierStylePara elsevierViewall">To further study the effect of the HPV vaccine on METTL3 expression in cSCC&#44; the authors overexpressed METTL3&#44; qPCR and Western blot were performed to detect the overexpression efficiency at mRNA and protein levels &#40;<a class="elsevierStyleCrossRef" href="#fig0035">Fig&#46; 7</a>A&#8210;B&#41;&#46; CCK-8 assay revealed that there was no significant difference in cell activity between the six groups within 24 hours of incubation&#46; After 96 hours of culture&#44; cell activity was significantly reduced when co-cultured with CD8<span class="elsevierStyleSup">&#43;</span>T cells and A431 cells compared with the control group&#44; and further reduced in A431 cell activity after the addition of HPV vaccine&#44; with statistical differences between all groups&#46; After overexpression of METTL3&#44; it still showed the inhibitory effect of CD8<span class="elsevierStyleSup">&#43;</span>T cells and HPV vaccine on A431 cell activity&#44; and A431 cell activity was significantly higher in the CD8<span class="elsevierStyleSup">&#43;</span>T cells&#43;HPV vaccine-OE-METTL3 group than in the CD8<span class="elsevierStyleSup">&#43;</span>T cells&#43;HPV vaccine-OE-NC group &#40;<a class="elsevierStyleCrossRef" href="#fig0040">Fig&#46; 8</a>A&#41;&#46; Also&#44; the authors examined m<span class="elsevierStyleSup">6</span>A in each group and found that HPV vaccine significantly reduced the total m<span class="elsevierStyleSup">6</span>A content in the co-culture system&#44; while METTL3 overexpression significantly abolished this effect&#46; Interestingly&#44; the m<span class="elsevierStyleSup">6</span>A content in the CD8<span class="elsevierStyleSup">&#43;</span>T cells&#43;HPV vaccine-OE-NC group was not statistically significantly different from Control -OE-NC&#44; while the m<span class="elsevierStyleSup">6</span>A content in the CD8<span class="elsevierStyleSup">&#43;</span>T cells -OE-NC group was elevated compared to Control -OE-NC&#44; although there was no statistical difference &#40;<a class="elsevierStyleCrossRef" href="#fig0040">Fig&#46; 8</a>B&#41;&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia><elsevierMultimedia ident="fig0040"></elsevierMultimedia></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Overexpression of METTL3 abolishes HPV vaccine inhibition of cSCC in vivo</span><p id="par0190" class="elsevierStylePara elsevierViewall">For further evaluation of METTL3 in the HPV vaccine against csCC&#44; xenograft tumor experiments were performed&#46; The authors divided the mouse models of cSCC into 4 groups of 5 mice each and gave PD-1 Abs&#43;OE-NC&#44; PD-1 Abs&#43;HPV vaccine&#43;OE-NC&#44; PD-1 Abs&#43;OE-METTL3&#44; and PD-1 Abs&#43;HPV vaccine&#43;OE-METTL3 treatments respectively&#46; In the combination of anti-PD-1 antibody and HPV vaccine&#44; tumor volume and weight were significantly reduced&#44; and co-treatment with HPV vaccination and anti-mouse PD-1 antibody resulted in complete inhibition of tumor growth&#44; while the inhibitory effect of anti-PD-1 antibody on tumor volume and weight was attenuated after overexpression of mettl3 &#40;<a class="elsevierStyleCrossRef" href="#fig0045">Fig&#46; 9</a>A&#8210;C&#41;&#46; Histologically&#44; it was found that the PD-1 Abs&#43;HPV vaccine&#43;OE-NC group had significantly more intratumoral infiltrates of CD8&#44; CD4&#44; NK&#44; DC&#44; and Macrophages than the other groups &#40;<a class="elsevierStyleCrossRef" href="#fig0050">Fig&#46; 10</a>A&#8210;B&#41;&#46;</p><elsevierMultimedia ident="fig0045"></elsevierMultimedia><elsevierMultimedia ident="fig0050"></elsevierMultimedia></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Discussion</span><p id="par0195" class="elsevierStylePara elsevierViewall">Immunosuppression is mainly manifested by diminished or absent proliferative capacity of T lymphocytes and dysfunctional cytokine secretion&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> CD8<span class="elsevierStyleSup">&#43;</span>T cells are immune cells that can recognize and kill cancer cells&#44; considered to have tumor-eradication potential&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> The present study found that the HPV vaccine enhanced the toxic effects of CD8<span class="elsevierStyleSup">&#43;</span>T cells on cSCC&#46; CD8<span class="elsevierStyleSup">&#43;</span>T cells are multiple cytokine producers and the HPV vaccine resulted in increased secretion of IFN-&#947;&#44; TNF-&#945;&#44; TGF-&#946;&#44; IL-17&#44; IL-33 by CD8<span class="elsevierStyleSup">&#43;</span>T cells&#46; Yunyan Sun concluded that both cervicovaginal vaccinations with TA-HPV could induce a strong local HPV-16E7 antigen-specific CD8<span class="elsevierStyleSup">&#43;</span>T cell immune response&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The present results suggest that after HPV vaccination in humans&#44; the body produces a certain amount of specific T-cell immune response along with antigen-antibody response&#44; and the resulting cytokines play a role in suppressing cutaneous squamous carcinoma cells&#44; suggesting that HPV vaccine may be better at stimulating antitumor immune response&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">RNA modifying enzymes are crucial for tumor survival in the process of immunotherapy&#44; and m<span class="elsevierStyleSup">6</span>A modifications play oncogenic roles in many cancers&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> The present results showed that overexpression of METTL3 in cSCC cells increased the level of m<span class="elsevierStyleSup">6</span>A modification in cSCC cells&#44; which confirmed the study of Renpeng Zhou from the side&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> indicating that METTL3 maintained m<span class="elsevierStyleSup">6</span>A modification in tumor cells and promoted the proliferative activity of cancer cells in cSCC&#46; Therefore&#44; the authors conclude that the HPV vaccine inhibits the development of squamous carcinoma by down-regulating METTL3&#44; probably because the downregulation of METTL3 expression increases the sensitivity of tumor cells to cytokines&#46; Lingling Wang suggested that high METTL3 expression status was negatively correlated with tumor immune cell infiltration&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> likewise&#44; the results showed that the immune infiltrating cells in cSCC tissues were significantly reduced after METTL3 overexpression in the animal experiment of this study&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">METTL3 may be a potential target for clinical treatment of cSCC&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Eliza Yankova demonstrated that a METTL3 inhibitor &#40;STM2457&#41; inhibits the carcinogenic effects caused by METTL3 enzyme overexpression in both in vitro cellular and in vivo animal experiments&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> lingling Wang demonstrated that depletion of the methyltransferases Mettl3 and Mettl14 enhanced response to anti-PD-1 treatment in colorectal cancer and melanoma&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Overexpression of METTL3 followed by treatment with PD-1 monoclonal antibodies did not show a significant trend of tumor regression in the present results&#44; whereas the HPV vaccine has the potential to act as a METTL3 inhibitor&#44; and the combination with PD-1 monoclonal antibodies for cSCC played a synergistic role to further slowdown the tumor growth&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">There is an urgent need to discover precise and effective targets for current therapeutic approaches in cSCC&#46; The main finding of this study was that HPV vaccine treatment of squamous carcinoma is correlated with METTL3 expression and also inhibited the formation of an immunosuppressive tumor microenvironment&#46; There are certain shortcomings in this study&#44; the sample size of clinical samples is small&#44; and sufficient samples may need to be collected for future studies&#44; while further use of m<span class="elsevierStyleSup">6</span>A sequencing and transcriptome sequencing may be needed to deeply explore the molecular regulatory mechanisms of METTL3-mediated HPV vaccine treatment for cSCC&#46; In conclusion&#44; the present experiments suggest that METTL3 is a promising target for the treatment of cSCC that can be downregulated by HPV vaccines&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conclusions</span><p id="par0215" class="elsevierStylePara elsevierViewall">The HPV vaccine enhances the sensitivity of anti-PD-1 treatment by down-regulating METTL3 in cutaneous squamous cell carcinoma&#46; The combination of HPV vaccine and PD-1 monoclonal antibody treatment produces an immune infiltration-enhancing effect&#44; resulting in better tumor control and promoting tumor clearance&#46; Overall&#44; this study provides some reference value for the in-depth exploration and research of the HPV vaccine&#46; In future studies&#44; research on the mechanistic aspects of METTL3 should be further strengthened&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Financial support</span><p id="par0220" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Authors&#8217; contributions</span><p id="par0225" class="elsevierStylePara elsevierViewall">Yingjie Zhang&#58; The study concept and design&#59; data collection&#44; or analysis and interpretation of data&#59; writing of the manuscript&#59; data collection&#44; analysis and interpretation&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Yiru Wang&#58; Data collection&#44; or analysis and interpretation of data&#59; data collection&#44; analysis&#44; and interpretation&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Shuping Guo&#58; Statistical analysis&#59; data collection&#44; analysis&#44; and interpretation&#59; effective participation in the research guidance&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Hongzhou Cui&#58; Critical review of important intellectual content&#59; effective participation in the research guidance&#59; critical review of the literature&#59; final approval of the final version of the manuscript&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conflicts of interest</span><p id="par0245" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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              "titulo" => "HPV vaccination enhances the infiltration of immune cells in human cSCC tissues"
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              "titulo" => "HPV vaccine enhances the killing ability of CD8T cells"
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              "titulo" => "METTL3-mediated HPV vaccine enhances susceptibility to cSCC immunotherapy"
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              "titulo" => "Overexpression of METTL3 abolishes HPV vaccine inhibition of cSCC in vivo"
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    "fechaRecibido" => "2023-03-16"
    "fechaAceptado" => "2023-05-02"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Cutaneous squamous cell carcinoma &#40;cSCC&#41; develops from epithelial keratinocytes by dysregulation of self-renewal and differentiation&#46; Recent studies have found that the size and number of cSCC tumors gradually decrease or even disappear after HPV vaccination&#46; However&#44; the role of the HPV vaccine in the cSCC mechanism is poorly understood&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">The aim of this study is to investigate the effect and mechanism of the HPV vaccine in cSCC&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Immunofluorescence was used to study the immune infiltrating cells in the tumor tissues of patients with cSCC&#46; The effects of the HPV vaccine on cSCC cells and tissues were studied by Cell Culture&#44; Real-time PCR&#44; Western Blot&#44; Cytotoxicity Assay&#44; Enzyme-linked Immunosorbent Assay&#44; m6A Blotting&#44; CCK-8 Assay&#44; m6A Ribonucleic acid Methylation Quantification and tumor transplantation&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">The HPV vaccine enhanced the toxic effect of CD8<span class="elsevierStyleSup">&#43;</span>T cells on cSCC cells and promoted the secretion of multiple cytokines by CD8<span class="elsevierStyleSup">&#43;</span>T cells&#46; In addition&#44; HPV vaccines can increase tumor sensitivity to anti-PD-1 therapy by downregulating METTL3 in tumor tissue&#44; with the combination of HPV vaccine and PD-1 monoclonal antibodies producing enhanced immune cell infiltration compared to PD-1 blockade alone&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Study limitations</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">It is important to note the limitations of this study&#44; including the small sample size&#44; the construction of the mouse model&#44; and the choice of HPV vaccine and PD-1 monoclonal antibody&#44; which may limit the generalization of our findings to a wider population&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclusions</span><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">It is hoped that this research will contribute to a deeper understanding of the role of the HPV vaccine in the treatment of cSCC&#46; HPV vaccine is expected to become an important approach to alleviate the development of cSCC&#46;</p></span>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Effect of overexpression of METTL3 on combination therapy in immunofluorescence&#46; &#40;A&#41; Immunofluorescence observation of immune microenvironment differences &#40;CD8&#44; CD4&#44; NK&#44; DC&#44; Macrophage&#41;&#59; &#40;B&#41; Image J statistical analysis of immune cell positive ratio&#46; &#42;&#42;&#42;p&#8239;&#60;&#8239;0&#46;001&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HPV vaccination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Site&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diameter&#40;cm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Procedure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anogenital areas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mohs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neck&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vermillion lips&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mohs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pretibial areas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Standard excision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3602794.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Details of human studies&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:34 [
            0 => array:3 [
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ISSN: 03650596
Original language: English
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