Immune checkpoint inhibition (ICI) improves outcomes in melanoma patients, but associated T-cell activation frequently leads to immune-related cutaneous adverse events (cutAEs). To dynamically identify T-cell subtypes and immune signatures associated with cutAEs, a pilot study was performed in stage III-IV melanoma patients using blood samples for flow cytometry and cytokine analysis. Blood samples were taken from patients before initiation of ICI (naive), at the onset of a cutAE, and after 6 months of ICI treatment. Overall, 30 patients were treated either with anti-PD1 monotherapy or with anti-PD-1/anti-CTLA-4 combination therapy. Flow cytometry analysis of PBMCs showed that ICI induced an overall shift from a Th2 towards a Th1 profile. Twelve patients (40%) developed cutAEs, which were associated with increased Th22 cells and Th17 cells, supported by a tendency to have elevated Th17/Th22-associated cytokines such as IL-17A, IL-22 and IL-23 levels in the plasma. Cytokine signatures specific for urticaria and T-cell-mediated cutAEs were identified in the plasma of patients by a bead-based assay. IL-10 was elevated in non-responders and, interestingly, during cutAEs. In conclusion, we identified distinct immune signatures based on the Th17/Th22 pathway in cutAEs, both in PBMCs and plasma. In addition, our finding of upregulated IL-10 during cutAEs supports the notion of treating these patients early and adequately to avoid implications for the overall outcome.
免疫检查点抑制剂（ICI）可改善黑色素瘤患者的预后，但相关的T细胞活化常导致免疫相关皮肤不良事件（cutAEs）。为动态识别与cutAEs相关的T细胞亚型及免疫特征，本研究对III-IV期黑色素瘤患者开展了一项探索性研究，通过采集血液样本进行流式细胞术和细胞因子分析。血液样本采集时间点包括：ICI治疗前（初治期）、cutAE发生时以及ICI治疗6个月后。共纳入30例患者，分别接受抗PD-1单药治疗或抗PD-1/抗CTLA-4联合治疗。外周血单个核细胞（PBMCs）流式分析显示，ICI诱导了免疫应答从Th2向Th1表型的整体偏移。12例患者（40%）出现cutAEs，其特征为Th22细胞和Th17细胞增多，且血浆中Th17/Th22相关细胞因子（如IL-17A、IL-22和IL-23）水平呈升高趋势。通过微球检测法在患者血浆中鉴定出荨麻疹特异性及T细胞介导型cutAEs的细胞因子特征谱。无应答者及（值得注意的是）cutAE发生期间IL-10水平升高。综上，我们在PBMCs和血浆中均发现基于Th17/Th22通路的cutAEs特异性免疫特征。此外，cutAE期间IL-10上调的发现支持早期充分治疗此类患者以避免影响整体预后的观点。
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