■针对程序性细胞死亡蛋白-1(PD-1)的生物制剂的免疫治疗在治疗各种恶性肿瘤中非常有效。然而,它经常导致意想不到的皮肤表现,包括牛皮癣样皮炎.抗PD-1型银屑病的发病机制尚待阐明,尽管一些先天和适应性免疫过程与典型的银屑病相似。患者对牛皮癣的遗传易感性也可能是一个促成因素。这里,我们调查了两名转移性黑色素瘤患者和一名肺癌患者的免疫学和遗传学特征,他们在接受抗PD-1纳武单抗治疗后患上了严重的银屑病。
■将这三名患者的免疫模式与经典,抗TNF-α治疗诱发的慢性斑块型银屑病或反常型银屑病,主要由适应性和先天免疫过程维持,分别。因此,对患者的皮肤活检进行了固有免疫和适应性免疫分子的免疫组织化学和mRNA分析。利用NGS技术对银屑病易感基因多态性进行了分析。
■我们发现抗PD-1诱导的银屑病表现出与慢性银屑病相似的免疫学特征,以适应性免疫的细胞球员的存在为特征,丰富的CD3+,CD8+T细胞和CD11c+树突状细胞浸润皮肤病变,并产生IL-23,IL-6,TNF-α,IFN-γ和IL-17。相反,较低数量的先天免疫细胞(BDCA2+浆细胞样树突状细胞,CD15+中性粒细胞,CD117+肥大细胞)和减少的IFN-α/β,淋巴毒素(LT)-α/β,在抗PD-1诱导的银屑病病变中观察到,与抗TNF-α诱导的矛盾型银屑病相比。重要的是,在抗PD-1治疗的患者的银屑病皮损中,含有去整合素和金属蛋白酶结构域的血小板反应蛋白1型基序样5(ADAMTSL5)银屑病自身抗原显著上调,水平与慢性斑块型银屑病相当。最后,NGS分析显示,所有患者在银屑病易感基因中携带几种等位基因变异,比如HLA-C,ERAP1等主要银屑病易感基因PSORS1位点。
■我们的研究表明,在抗PD-1诱导的银屑病病变中,适应性免疫优于先天免疫,与局部ADAMTSL5过表达一致。三名患者的牛皮癣易感基因中存在许多SNP也表明他们对该疾病的强烈倾向。
Immunotherapy with biologics targeting programmed cell death protein-1 (PD-1) is highly effective in the treatment of various malignancies. Nevertheless, it is frequently responsible for unexpected cutaneous manifestations, including psoriasis-like dermatitis. The pathogenesis of anti-PD-1-induced psoriasis has yet to be clarified, even though it is plausible that some innate and adaptive immunity processes are in common with canonical psoriasis. The genetic predisposition to psoriasis of patients could also be a contributing factor. Here, we investigated the immunological and genetic profiles of two patients with metastatic melanoma and one patient affected by lung cancer, who developed severe psoriasis after receiving anti-PD-1 nivolumab therapy.
The immune patterns of the three patients were compared with those detectable in classical, chronic plaque-type psoriasis or paradoxical psoriasis induced by anti-TNF-α therapy, mostly sustained by adaptive and innate immunity processes, respectively. Therefore, immunohistochemistry and mRNA analyses of innate and adaptive immunity molecules were conducted on skin biopsy of patients. Genetic analysis of polymorphisms predisposing to psoriasis was carried out by NGS technology.
We found that anti-PD-1-induced psoriasis showed immunological features similar to chronic psoriasis, characterized by the presence of cellular players of adaptive immunity, with abundant CD3+, CD8+ T cells and CD11c+ dendritic cells infiltrating skin lesions, and producing IL-23, IL-6, TNF-α, IFN-γ and IL-17. On the contrary, a lower number of innate immunity cells (BDCA2+ plasmacytoid dendritic cells, CD15+ neutrophils, CD117+ mast cells) and reduced IFN-α/β, lymphotoxin (LT)-α/β, were observed in anti-PD-1-induced psoriasis lesions, as compared with anti-TNF-α-induced paradoxical psoriasis. Importantly, the disintegrin and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5) psoriasis autoantigen was significantly upregulated in psoriasis lesions of anti-PD-1-treated patients, at levels comparable with chronic plaque-type psoriasis. Finally, NGS analysis revealed that all patients carried several allelic variants in psoriasis susceptibility genes, such as HLA-C, ERAP1 and other genes of the major psoriasis susceptibility PSORS1 locus.
Our study showed that adaptive immunity predominates over innate immunity in anti-PD-1-induced psoriasis lesions, consistently with the local ADAMTSL5 overexpression. The presence of numerous SNPs in psoriasis susceptibility genes of the three patients also suggested their strong predisposition to the disease.