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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">TRMs express PD-1 in psoriasis&#46; PD-1 and IL-17A were costained with CD4&#44; CD8&#44; or TCR &#947;&#948;&#46; White arrowheads indicate triple-stained cells&#44; and a tailed white arrow indicates IL-17A-PD-1<span class="elsevierStyleSup">&#43;</span> CD8 T-cells&#46; Reproduced with the permission of Copyright Clearance Center&#64;Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL-17A production from programmed cell death 1-high T-cells&#46;</p>"
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prediction and diagnosis&#44; possible mechanisms&#44; and treatment principles&#46; The aim is to improve the recognition and effective individualized management of these cirAEs by dermatologists to ensure the quality of life for cancer patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Checkpoint PD-1 in the maintenance of T-cell homeostasis</span><p id="par0010" class="elsevierStylePara elsevierViewall">It is now clear that T-cell activation is tightly regulated by a &#8220;dual channel&#8221; to avoid under- or over-reaction&#46; The first signal refers to the specific binding of the T-Cell Receptor &#40;TCR&#41; to the Major Histocompatibility Complex &#40;MHC&#41; of the Antigen-Presenting Cells &#40;APCs&#41;&#46; The second signal refers to the interactions of immune checkpoint molecules &#40;co-stimulatory and co-inhibitory molecules&#41; on the surface of the T-cells and APCs&#46; Co-inhibitory immune checkpoints are a class of immunosuppressive molecules that include programmed death receptors and their ligands&#46; They can prevent sustained immune responses&#44; thus avoiding damage and destruction of normal tissues&#46; Common co-suppressive immune checkpoints include PD-1&#44; CTLA-4 &#40;Cytotoxic T-Lymphocyte-Associated Protein 4&#41;&#44; VISTA &#40;V-domain Ig Suppressor of T-cell Activation&#41;&#44; TIM &#40;CD366&#59; HAVCR2&#41; and LAG-3 &#40;Lymphocyte Activation Gene 3&#41;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">PD-1 is a co-inhibitory immune checkpoint that is widely targeted in clinical therapy&#46; The human PD-1 gene is located on chromosome 2q37&#46;3&#46; It is a transmembrane protein molecule consisting of 288 amino acid residues&#46; It belongs to the immunoglobulin superfamily&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> As a regulatory receptor&#44; it is mainly expressed on activated CD4&#43; and CD8&#43; T-cells&#46; Unactivated T-cells do not express high-level PD-1&#46; PD-1 is also expressed on B cells&#44; NKT cells&#44; dendritic cells and monocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The PD-1 molecule binds mainly to its ligand PD-L1 &#40;B7-H1&#41; or PD-L2 &#40;B7-DC&#41;&#46; PD-L1 and PD-L2 can be expressed in tumor cells&#44; dendritic cells&#44; macrophages&#44; and vascular endothelial cells&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The binding of PD-1 to the ligand inhibits the TCR signaling pathway mediated by the tyrosine phosphatase SHP2&#46; By providing negative costimulatory signals&#44; it inhibits T-cell activation and proliferation&#44; leading to reduced T-cell function&#44; loss of activity&#44; and&#47;or apoptosis&#46; It can be seen that PD-1 plays an important role in the establishment of peripheral immune tolerance&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">PD-1 checkpoint inhibitors and their irAEs in tumor targeting therapy</span><p id="par0025" class="elsevierStylePara elsevierViewall">Tumor cells express PD-L1 and thus exploit the normal physiological checkpoints of immune cells for immunosuppression&#46; This can lead to an imbalance between tumor growth and host surveillance&#44; so anti-PD-1 drugs may reverse the inhibitory signal from tumor cells to immune cells&#44; particularly CD8&#43; T-cells&#46; In 2010&#44; scientists reported the first study of anti-PD-1 antibodies in solid tumors&#44; including 39 patients with advanced melanoma&#44; non-small cell lung cancer&#44; renal cell carcinoma&#44; prostate cancer and colorectal cancer treated with MDX1106 &#40;nivolumab&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Currently&#44; nivolumab and pembrolizumab are the most widely used anti-PD-1 antibodies in clinical practice&#46; They have shown significant therapeutic efficacy in a wide range of tumors&#44; including advanced melanoma&#44; non-small cell lung cancer&#44; renal cell carcinoma&#44; bladder cancer&#44; and Hodgkin&#39;s lymphoma&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Immune-related adverse events may occur in the targeted therapy of tumors&#44; known as irAEs&#46; irAEs have the following characteristics&#58; &#40;i&#41; Organ specificity&#58; irAEs can affect almost any organ system in the body&#44; but the most commonly affected tissues are the body&#39;s barrier tissues&#44; such as the skin&#44; gastrointestinal tract&#44; liver and respiratory epithelium&#59; &#40;ii&#41; Their delayed onset and long-term persistence&#58; although the mean time to onset of irAEs varies among individuals&#44; they all have the characteristic of delayed onset&#44; typically occurring weeks even months after drug administration&#59;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> &#40;iii&#41; Inflammatory memory background&#58; patients with a concomitant or previous inflammatory disease are more likely to develop irAEs&#59; &#40;iv&#41; Reversibility&#58; 70&#37; of irAEs are mild to moderate and most resolve after discontinuation of the drug or use of corticosteroids&#59;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;10</span></a> &#40;v&#41; Tumor type heterogeneity&#58; the same immune checkpoint inhibitors &#40;ICIs&#41; may produce different toxicity profiles when used to treat different tumors&#59; &#40;vi&#41; ICI-related incidence&#58; anti-CTLA-4 results in a higher overall incidence of irAEs than anti-PD-l&#46; The incidence of irAEs increased when the combination was administered&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Common irAEs include dermal toxicity&#44; endocrine toxicity&#44; hepatotoxicity and immune-related pneumonia&#44; being skin-related the most common irAEs&#59; on the other hand&#44; cardiac and nephrotoxicity are rare irAEs events&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;14</span></a> The incidence of cutaneous toxicity due to anti-CTLA-4 and anti-PD-1 is 50&#37; and 30&#37;&#8210;40&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Cutaneous irAEs may manifest as non-specific rash&#44; psoriasis&#44; vitiligo&#44; lichenoid dermatitis&#44; pemphigus&#44; aspergillosis&#44; dermatomyositis&#44; and severe drug rash&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">The characteristics of psoriasis <span class="elsevierStyleItalic">de novo</span> or exacerbation by PD-1 checkpoint inhibitors</span><p id="par0040" class="elsevierStylePara elsevierViewall">PD-1-induced psoriasis can be either <span class="elsevierStyleItalic">de novo</span> &#40;55&#46;0&#37;&#41; or an exacerbation of pre-existing psoriasis&#46; The most common clinical type is plaque psoriasis &#40;70&#46;6&#37;&#41;&#44; with guttate psoriasis &#40;21&#46;4&#37;&#41; and rare pustular and reverse psoriasis manifestations&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#8211;18</span></a> Furthermore&#44; the involvement of palmoplantar areas can be found in 38&#46;3&#37; of PD-1-induced psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Psoriasis&#44; as a cirAE caused by PD-1 inhibitor&#44; currently lacks effective prediction tools&#44; and it is difficult to achieve model prediction for its occurrence in tumor patients who use ICIs&#46; However&#44; integrating factors related to the disease may be helpful for its diagnosis&#58; &#40;i&#41; Concomitant psoriasis or history&#47;family history of psoriasis&#59; &#40;ii&#41; Psoriatic lesions appearing or exacerbation on average 5&#8210;12 weeks or longer after the start of ICI therapy&#59;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a> &#40;iii&#41; Matching the distribution and lesion characteristics of classic psoriatic lesions&#59;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;24</span></a> &#40;iv&#41; The histopathological features of PD-1 inhibitor-related psoriasis are not significantly different from those of classic psoriasis&#46; However&#44; drug-induced psoriasis usually lacks significantly dilated dermal papillary capillaries and thinning of the papillary upper epidermis&#59;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a> &#40;v&#41; Psoriasis treatment protocol is effective for the lesions&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Studies have shown that those tumor patients who developed irAE had better outcomes than those who did not develop irAE&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;28</span></a> In a study with 7008 tumor patients&#44; those with concomitant psoriasis had better survival than patients without psoriasis &#40;HR&#8239;&#61;&#8239;0&#46;703&#59; 95&#37; Confidence Interval 0&#46;497&#8210;0&#46;994&#59; p&#8239;&#61;&#8239;0&#46;045&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The development of psoriasis&#44; a complication of PD-1 inhibitors&#44; may be a reflection of a good response to tumor PD-1 inhibitor treatment&#46; However&#44; this conclusion needs to be supported by studies with larger sample sizes&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">The theoretical mechanism of psoriasis <span class="elsevierStyleItalic">de novo</span> or exacerbation by PD-1 checkpoint inhibitors</span><p id="par0055" class="elsevierStylePara elsevierViewall">Since PD-1 inhibitors can reduce or release the &#8220;brakes&#8221; on the immune response&#44; they can theoretically activate the innate and adaptive immune systems&#46; The cells that may be affected by PD-1 inhibitors include dendritic cells&#44; Th cells&#44; and Treg cells&#46; The cytokines they secrete&#44; especially interferon-gamma&#44; IL-1&#44; IL-17&#44; and IL-22&#44; may play a vital role in the pathogenesis of psoriasis <span class="elsevierStyleItalic">de novo</span> or exacerbation&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> However&#44; the exact mechanisms need to be verified by further studies&#46; Here the authors present a step-by-step theoretical analysis of the potential effects of PD-1 inhibitors on the innate and adaptive immune systems&#46;</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Effects of PD-1 inhibitors on the innate immune system</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Potential effects of PD-1 inhibitors on neutrophils</span><p id="par0060" class="elsevierStylePara elsevierViewall">As a key driver of the innate immune response&#44; neutrophils play an important role in the axis of psoriasis pathogenesis&#46; Neutrophils shuttle out of the blood vessels and migrate into the epidermis to form the Munro or Kogoj microabscess&#44; the typical pathological feature of psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Currently&#44; it is believed that neutrophils secrete various cytokines and chemokines such as TNF-&#945;&#44; IL-17&#44; and IL-36 family factors&#44; as well as neutrophil extracellular traps &#40;NETs&#41; and neutrophil exosomes&#44; directly or indirectly involved in the pathogenesis of psoriasis&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The PD-L1&#47;PD-1 pathway is involved in the regulation of neutrophil apoptosis&#46; PD-L1 on neutrophils contains a structure similar to tyrosine-X-X-Methionine &#40;YXXM&#41;&#44; which promotes the binding of Phosphatidylinositol 3-Kinase &#40;PI3K&#41; and activates the p85 subunit&#46; The latter regulates apoptosis of the neutrophils themselves&#44; thereby prolonging their activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> Thus&#44; anti-PD-1 antibodies may prolong neutrophil activity and are likely to participate in the onset and maintenance of psoriasis through the aforementioned pathways&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Potential effects of PD-1 inhibitors on dendritic cells</span><p id="par0070" class="elsevierStylePara elsevierViewall">There are three types of dendritic cells &#40;DCs&#41; in psoriasis lesions&#58; langerhans cells &#40;LCs&#41;&#44; plasmacytoid dendritic cells &#40;pDCs&#41; and myeloid dendritic cells &#40;mDCs&#41;&#46; The former are mainly found in the epidermis of psoriatic lesions&#44; while the latter two are mainly found in the dermis&#44; and all three play a pathogenic role in psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">At present&#44; there is no investigation to elucidate the mechanism of DCs in psoriasis induced by PD-1 inhibitors&#44; but the authors can obtain clues from research in the field of oncology&#46; It has been shown that PD-L1 can be expressed on tumor cells and Tumor-Infiltrating Immune Cells &#40;TICs&#41;&#44; particularly macrophages and myeloid DCs&#46; PD-1&#47;PD-L1 signal in tumor microenvironment can mediate the inhibition of T-cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> PD-1 inhibitors have been demonstrated to directly induce Interferon &#947; &#40;IFN-&#947;&#41; production of activated T-cells&#44; which induces IL-12 production by intra-tumor DC subpopulations&#46; IL-12 is involved in both anti-tumor T-cell immunity and stimulates massive T-cell proliferation while secreting various cytokines to form a positive feedback inflammatory loop&#46; In addition&#44; IL-12 can inhibit <span class="elsevierStyleItalic">Eomes</span>&#44; a key regulator of T-cell exhaustion&#44; resulting in reduced T-cell exhaustion&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Similarly&#44; the authors know that IL-12 is also one of the factors that play an important role in the onset and development of psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> However&#44; research is needed to confirm whether these mechanisms are related to the involvement of DCs in the induction or exacerbation of psoriasis by PD-1 inhibitors&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Potential effects of PD-1 inhibitors on macrophages</span><p id="par0080" class="elsevierStylePara elsevierViewall">Macrophages&#44; as one of the key cells of innate immunity&#44; have the role of producing inflammatory mediators&#44; presenting antigens&#44; phagocytosis&#44; and killing pathogenic microorganisms&#46; According to their immune function&#44; they can be divided into M1-type macrophages&#44; i&#46;e&#46; classically activated macrophages&#44; and M2-type macrophages&#44; i&#46;e&#46; alternatively activated macrophages&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> In terms of immune function&#44; M1-type macrophages and M2-type macrophages represent two extremes&#46; M1 activation mainly secretes some pro-inflammatory factors that help Th1 cells in their anti-infective function&#46; In contrast&#44; M2 activation is mainly involved in fibrosis&#44; tissue repair&#44; and humoral immunity and is an &#39;anti-inflammatory&#39; macrophage&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Macrophages are involved in the development of psoriasis&#46; First&#44; macrophages are increased in psoriatic lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> They can induce excessive proliferation and abnormal differentiation of keratinocytes by secreting cytokines such as TNF-&#945;&#44; MIF and IL-20&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#8211;45</span></a> Second&#44; macrophages promote psoriatic angiogenesis by upregulating the expression of Vascular Endothelial Growth Factor &#40;VEGF&#41;&#44; TGF-&#946;&#44; Platelet-Derived Growth Factor &#40;PDGF&#41;&#44; and TNF-&#945;&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> In addition&#44; macrophages also play a role in positive feedback of inflammatory factors &#40;e&#46;g&#46;&#44; IL-1 and prokineticin 2&#41; in psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">PD-1 has been found to be expressed on macrophages and mediates macrophage apoptosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#8211;50</span></a> In the treatment of tumors&#44; the use of PD-1 inhibitors can attenuate this effect and increase the number of macrophages&#46; In addition&#44; Tumor-Associated Macrophages &#40;TAMs&#41; have plasticity and can differentiate into the inflammatory M1 type or the M2 type&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#8211;53</span></a> PD-1&#43; TAMs have similar surface molecular expression patterns and functions to M2-type macrophages&#44; such as persistently enhanced expression of CD206 and IL-10&#44; reduced expression of HLA-DR&#44; CD64 and IL-12&#44; and significantly enhanced ability to suppress CD8&#8239;&#43;&#8239;T-cells&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> In contrast&#44; the expression profile of PD-1-TAMs was similar to that of M1-type macrophages&#46; Their number and the anti-inflammatory function of PD-1&#43; TAMs were suppressed after the use of PD-1 inhibitors&#46; However&#44; whether the above is involved in the development or exacerbation of psoriasis needs to be verified by relevant experiments&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Effects of PD-1 inhibitors on the adaptive immune system</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Potential effects of PD-1 inhibitors on Th1 and Th17 cells</span><p id="par0095" class="elsevierStylePara elsevierViewall">Classical psoriasis is generally considered as a Th1 and Th17 disease&#46; It has been demonstrated that in plaque psoriasis&#44; cytokines of the Th1 pathway &#40;IL-2&#44; IL-12&#44; IF-&#947;&#41; and Th17A pathway &#40;IL-17A&#44; IL-17F&#44; IL-21&#44; IL-22&#41; play a major role in the recruitment of more immune cells&#44; leading to persistent inflammatory infiltration and proliferation of keratinocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">55&#44;56</span></a> T-cells commonly express PD-1 and PD-L1&#44; and treatment with anti-PD-1 antibodies has a dramatic effect on T-cell-mediated adaptive immunogenesis&#46; This is often considered to be the main cause of psoriasis onset or exacerbation by anti-PD-1 antibodies&#46; Below the authors analyze it from the perspectives of proliferation&#44; differentiation&#44; and function of T-cells&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In terms of proliferation&#44; Lebwohl et al&#46; suggested that reduced PD-L1 expression in the psoriatic epidermis may allow continuous activation of T cells&#46; This was confirmed by immunohistochemical staining&#44; where PD-L1 expression levels were reduced on average in the psoriatic epidermis for both mRNA and protein&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#8211;61</span></a> However&#44; there are reports of &#8220;clonal shrinkage&#8221; after anti-PD-1 treatment&#44; i&#46;e&#46; T-cell activation clones do not appear or even disappear&#44; the mechanisms of which need to be further investigated&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> It is currently known that in a culture system in which PHA &#40;phytohaemagglutinin&#41; stimulates T-cell proliferation&#44; PD-L1 blocks T-cell proliferation in the G0&#47;G1 phase&#44; down-regulates T-cell activation&#44; inhibits T-lymphocyte responsiveness to PHA proliferation and thus reduces T-cell proliferation&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In terms of differentiation&#44; the authors know that Th1 and Th17 cells are the pro-immune cells&#44; while Th2 cells are the suppressor cells of psoriatic inflammation&#46; Blocking the PD-1&#47;PD-L pathway not only promotes T-cell proliferation but also induces the differentiation of CD4&#43; T-cells into Th1 and Th17 cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">63&#44;64</span></a> After PD-1 blocking&#44; T-cells have been demonstrated to exhibit multiple differentiation trajectories&#46; Among them&#44; there is an important differentiation trajectory&#44; which is the trajectory of na&#239;ve T-cells &#8594; Th1 cells&#44; or Tfh cells&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> This may have important implications for exploring the mechanism of psoriasis <span class="elsevierStyleItalic">de novo</span> or exacerbation by PD-1 checkpoint inhibitors&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In terms of function&#44; the effector properties of CD4&#43; and CD8&#43; T-cells are enhanced after PD-L1 blockade treatment&#46; Research has found that after anti-PD-L1 treatment&#44; T-cells chemotactic to CXCL13 exhibit enhanced cytotoxicity&#44; as well as enhancement of IFN-&#947; signal pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Potential effect of PD-1 inhibitors on regulatory T cells</span><p id="par0115" class="elsevierStylePara elsevierViewall">The effect of PD1&#47;PD-L1 on the regulation of regulatory T-cells &#40;Treg&#41; is mainly reflected in the following aspects&#46; First&#44; it has been shown that PD-L1-coated microbeads can induce Treg in vitro&#44; and PD-L1 can increase Foxp 3 expression and enhance the immunosuppressive capacity of Treg&#46; <a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In addition&#44; PD-Ll can promote the conversion of na&#239;ve CD 4&#43; T-cells into Treg by downregulating Akt&#44; mTOR and ERK 2 as well as upregulating PTEN at the same time&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> Second&#44; the regulation of PD-1 is affected by the Notch pathway&#44; and the differentiation and function of Treg also require the participation of the Notch pathway&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">68&#8211;70</span></a> Overexpression of Jagl&#44; a ligand of the Notch pathway&#44; on DCs&#44; increases PD-Ll expression&#44; and co-culture of CD 4&#43; T-cells with these Jagl-DCs promotes Treg generation&#44; while PD-Ll blockade partially reduces Treg amplification&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> The above findings confirm the important role of PD-1 in the induction of Treg amplification&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Furthermore&#44; the immunomodulatory capacity of Treg is reduced in ICI-induced pneumonia&#44; and it is speculated that diminished immunosuppression of Treg may induce a more intense Th1 immune response in ICI-induced pneumonia&#44; and it can be ventured to speculate that this response may also play a role in the formation of psoriatic lesion plaques&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">In a word&#44; antagonizing PD1&#47;PD-L1 can weaken the quantity and function of Treg&#44; possibly leading to an imbalance between Treg and Th1&#47;Th17 cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">73&#8211;76</span></a> Therefore&#44; it can theoretically lead to the occurrence or exacerbation of psoriasis&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">The potential effect of PD-1 inhibitor on tissue-resident memory T-cells</span><p id="par0130" class="elsevierStylePara elsevierViewall">Memory T-cells&#44; based on their migratory behavior&#44; are divided into circulating memory T-cells and Tissue-Resident Memory T-cells &#40;TRMs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> TRMs generally do not re-enter the bloodstream and persist in peripheral tissues such as epithelial barriers &#40;the skin&#44; the lung&#44; the gastrointestinal tract&#44; and the reproductive tract&#41; and internal organs &#40;kidney&#44; brain&#41;&#44; where they can provide long-term immune protection against infection&#44; tumor&#44; and other tissue damage&#46; TRMs are characterized by adhesion molecule CD103 &#40;aE integrin subunit&#41; and&#47;or activation marker CD69&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78&#8211;80</span></a> TRMs have prominent characteristics of long lifespan and low mobility&#44; as well as unique transcriptional profiles&#46; They are usually believed to be involved in the recurrence of psoriasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">81&#8211;83</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">TRMs express PD-1 and PD-L1&#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; suggesting that anti-PD-1&#47;PD-L1 drugs can act on TRMs&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> The involvement of anti-PD-1 antibodies in the occurrence&#47;exacerbation of psoriasis may be related to the following mechanisms&#58; &#40;i&#41; Anti PD-1 therapy enhances the cytotoxic effect of CD103&#43;TRMs&#59;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> &#40;ii&#41; Anti PD-1 antibody enables the amplification of TRM clones and enhances the expression of IFN-&#947; and IL-17 that can initiate&#47;exacerbate psoriasis&#59;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> &#40;iii&#41; PD-1 antibody blockade enhances the interaction and co-activation of TRM with circulating memory cells&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Treatment of psoriasis induced or aggravated by PD-1 inhibitors</span><p id="par0140" class="elsevierStylePara elsevierViewall">In 2022&#44; the EADV Working Group put forward management requirements and basic principles&#58; medical interventions should vary from person to person&#59; on the premise of alleviating irAEs and improving the quality of life&#44; the patients&#39; targeted therapy should be continued or adjusted&#46; A new balance should be established between irAE treatment and targeted therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a> Once psoriasis induced or aggravated by PD-1 inhibitors is diagnosed&#44; dermatologists should be invited to participate in early treatment and management in accordance with interdisciplinary principles&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">87&#44;88</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Psoriasis due to ICIs &#40;immune checkpoint inhibitors&#41; can be classified as Grade I&#44; Grade II and Grade III according to the Common Criteria for the Evaluation of Adverse Events &#40;CTCAE v5&#46;0&#41; classification&#46; The majority of these patients are in Grade I or II&#44; and only a few reach Grade III&#44; which is in accordance with the &#8220;pyramid&#8221; pattern&#46; According to the latest management standards by the EADV working group&#58; Patients with Grade 1 should receive topical treatment modalities such as potent corticosteroids and vitamin D analogs while maintaining their current ICI dose&#59; Grade II patients should be treated with traditional systemic therapies such as phototherapy and retinoids on the basis of Grade I management&#44; with continuation or adjustment of ICI dose&#46; Their grading needs to be re-evaluated two weeks later&#59; Grade III patients should be treated with increased doses of traditional systemic therapy based on Grade II management&#46; If ineffective or deteriorating&#44; biologics &#40;e&#46;g&#46;&#44; TNF-&#945; antagonists&#41; can be considered&#44; and the ICI regimen should be adjusted at the same time&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a> These differ markedly from the principles of management of traditional drug-induced psoriasis&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">In the course of treatment&#44; we should also pay attention to another issue&#46; In the past&#44; oncologists often recommended systemic corticosteroids for severe irAEs&#44; however&#44; the American Academy of Dermatology-National Psoriasis Foundation do not recommend it for psoriasis <span class="elsevierStyleItalic">de novo</span> or exacerbation by PD-1 checkpoint inhibitors&#46; This is because systemic corticosteroids lack lasting efficacy and may cause psoriasis relapse when tapering&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a> Also&#44; due to the presence of malignant neoplastic disease&#44; patients are advised to avoid cyclosporine and some biological agents and small molecule inhibitors &#40;e&#46;g&#46;&#44; Jak inhibitors&#41; that may induce&#47;exacerbate tumor progression&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a> While receiving treatments&#44; patients should also avoid factors that may induce or aggravate psoriasis&#44; such as stress&#44; obesity&#44; alcoholism&#44; smoking and infection&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Taken together&#44; we need to take into account both the following aspects&#58; &#40;1&#41; The appearance of skin irAEs may be an indicator of good anti-tumor efficacy of ICIs&#44; and &#40;2&#41; The possibility of psoriatic lesion recurrence or even worsening by continued immunotherapy&#59;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">91&#8211;93</span></a> In addition&#44; the authors need to take into account that the treatment regimen adopted should be effective against cutaneous irAEs&#44; but also that the regimen should not negatively affect antitumor immunity&#46; Therefore&#44; physicians need to make individualized decisions and fully assess the risks and benefits&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Summary</span><p id="par0160" class="elsevierStylePara elsevierViewall">With the wide application of tumor immunotherapy&#44; the occurrence of skin adverse reactions becomes more and more frequent&#46; It has been a challenge for both oncologists and dermatologists to standardize the management of skin adverse reactions while minimizing the impact on immunotherapy&#46; What the authors present here is an overview of the current status of psoriasis <span class="elsevierStyleItalic">de novo</span> or exacerbation by PD-1 checkpoint inhibitors&#46; The authors can see that there are some aspects of this field that we need to further elucidate&#44; such as what are the exact molecular mechanisms by which PD-1 inhibitors trigger&#47;exacerbate psoriasis&#46; Do these mechanisms differ and intersect with those of classical psoriasis&#63; Are there differences in the clinical phenotypes and molecular mechanisms by which different PD-1 inhibitors trigger&#47;exacerbate psoriasis&#63; Is it appropriate that methotrexate is proposed to be used in the treatment of psoriasis associated with PD-1 inhibitors&#44; as methotrexate may cause Methotrexate-associated Lymphoproliferative Disorder &#40;MTX-LPD&#41; in individuals with unstable immune microenvironment&#63; The resolution of the above questions will better facilitate our effective and safe treatment of numerous skin irAEs by PD-1 inhibitors&#44; including psoriasis&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Financial support</span><p id="par0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleGrantSponsor" id="gs0005">National Natural Science Foundation of China</span> &#40;n&#186; <span class="elsevierStyleGrantNumber" refid="gs0005">82273537</span>&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Authors&#8217; contributions</span><p id="par0170" class="elsevierStylePara elsevierViewall">Zhu Shen&#58; Conceived and designed the study&#44; critically revised the manuscript&#44; and approved the final version of the manuscript and the publication&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Zi Wan&#58; Searched the literature&#44; wrote the paper&#44; and approved the final version of the manuscript and the publication&#59; Approval of the final version of the manuscript&#59; Study conception and planning&#59; Preparation and writing of the manuscript&#59; Manuscript critical review&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Jiangyuan Huang&#58; Searched the literature&#44; wrote the paper&#44; and wrote the paper and approved the final version of the manuscript and the publication&#59; Approval of the final version of the manuscript&#59; Study conception and planning&#59; Preparation and writing of the manuscript&#59; Manuscript critical review&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Xiaojie Ou&#58; Searched the literature and wrote the paper and wrote the paper and approved the final version of the manuscript and the publication&#59; Approval of the final version of the manuscript&#59; Study conception and planning&#59; Preparation and writing of the manuscript&#59; Manuscript critical review&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Shuang Lou&#58; Searched the literature&#44; wrote the paper&#44; and approved the final version of the manuscript and the publication&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Jianji Wan&#58; Searched the literature&#44; critically revised the manuscript&#44; and approved the final version of the manuscript and the publication&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of interest</span><p id="par0200" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">PD-1 &#40;programmed Death-1&#41; immune checkpoint inhibitors have provided significant benefits to tumor patients&#46; However&#44; a considerable proportion of the patients develop immune-related adverse events &#40;irAEs&#41;&#44; of which cutaneous irAEs &#40;cirAEs&#44; e&#46;g&#46;&#44; psoriasis&#41; occur relatively early&#46; This review provides an overview of the current progress in psoriasis <span class="elsevierStyleItalic">de novo</span> or exacerbation by PD-1 checkpoint inhibitors&#46; It not only describes the relevant influencing factors but also theoretically analyzes the immunological mechanisms that lead to the onset or exacerbation of psoriasis&#46; Finally&#44; the authors present guidelines for the treatment of psoriasis <span class="elsevierStyleItalic">de novo</span> or exacerbation by PD-1 checkpoint inhibitors&#46; The review is intended to assist dermatologists in the early recognition and effective individualized management of such cirAE&#44; which is helpful to continue or adjust the tumor-targeted immunotherapy on the basis of ensuring the quality of life of tumor patients&#46;</p></span>"
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