Purpose: Immune-related cutaneous adverse events (ircAEs) occur in ≥50% of patients treated with checkpoint inhibitors (CPI), but mechanisms are poorly understood. Experimental Design: Phenotyping/biomarker analyses were conducted in 200 patients on CPIs (139 with ircAEs, 61 without, control) to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip (STS) extracts and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays. Results: Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFN-gamma mRNA in patients with lichenoid (p<0.0001) and psoriasiform dermatitis (p<0.01) as compared to patients without ircAEs, while the highest IL-13 mRNA levels were detected in the eczema (p<0.0001, compared to control). IL-17A mRNA was selectively increased in psoriasiform (p<0.001), lichenoid (p<0.0001), bullous dermatitis (p<0.05) and MPR (p<0.001), compared to control. Distinct cytokine profiles were confirmed in STS and plasma. Analysis determined increased skin/plasma IL-4 cytokine in pruritus, skin IL-13 in eczema, plasma IL-5 and IL-31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2-cytokine targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo. Conclusions: Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.

中文翻译：

---

使用检查点抑制剂对免疫相关皮肤不良事件进行免疫学分析，揭示极化的可行途径

目的：≥50%接受检查点抑制剂（CPI）治疗的患者会发生免疫相关皮肤不良事件（ircAE），但其机制尚不清楚。实验设计：对 200 名 CPI 患者（139 名有 ircAE，61 名没有对照）进行表型/生物标志物分析，以表征他们的临床表现和免疫内型。使用实时 PCR 和 Meso Scale Discovery 多重细胞因子测定法评估皮肤活检、皮肤胶带 (STS) 提取物和血浆中的细胞因子。结果：确定了 8 种 ircAE 表型：瘙痒 (26%)、斑丘疹 (MPR；21%)、湿疹 (19%)、苔藓样 (11%)、荨麻疹 (8%)、银屑病 (6%)、白癜风 (5 %) 和大疱性皮炎 (4%)。所有表型均显示皮肤淋巴细胞和嗜酸性粒细胞浸润。皮肤活检 PCR 显示，与无 ircAE 的患者相比，患有苔藓样皮炎 (p<0.0001) 和银屑病样皮炎 (p<0.01) 的患者 IFN-gamma mRNA 水平最高，而湿疹患者中检测到最高的 IL-13 mRNA 水平。与对照相比，p＜0.0001)。与对照相比，IL-17A mRNA在银屑病样(p＜0.001)、苔藓样皮炎(p＜0.0001)、大疱性皮炎(p＜0.05)和MPR(p＜0.001)中选择性增加。 STS 和血浆中证实了不同的细胞因子谱。分析确定瘙痒症中皮肤/血浆 IL-4 细胞因子增加，湿疹中皮肤 IL-13 增加，湿疹和荨麻疹中血浆 IL-5 和 IL-31 增加，MPR 中混合细胞因子途径增加。通过皮质类固醇或 2 型细胞因子靶向抑制进行广泛抑制，可在这些 ircAE 中带来临床益处。相比之下，在银屑病、苔藓样皮炎、大疱性皮炎和白癜风中的 1 型激活中发现了 1 型/17 型通路的显着皮肤上调。结论：独特的免疫学 ircAE 内型表明了基于精准医学的干预措施的可行目标。