Although anti-programmed death-1 (PD-1) treatment has shown remarkable anti-tumor efficacy, immune-related adverse events (irAEs) develop with heterogeneous clinical manifestations. However, the immunological understanding of irAEs is currently limited. In the present study, we analyzed peripheral blood T cells obtained from cancer patients who received anti-PD-1 treatment to determine the immunological characteristics of irAEs. This study included 31 patients with refractory thymic epithelial tumor (TET) who were enrolled in a phase II trial of pembrolizumab (NCT02607631) and 60 patients with metastatic non-small cell lung cancer (NSCLC) who received pembrolizumab or nivolumab. T-cell profiling was performed by multicolor flow cytometry using peripheral blood obtained before treatment and 7 days after the first dose of anti-PD-1 antibodies. irAEs developed in 21 TET patients and 24 NSCLC patients. Severe (≥ grade 3) irAEs occurred in 7 TET patients (22.6%) and 6 NSCLC patients (10.0%). Patients with severe irAEs exhibited a significantly lower fold increase in the frequency of effector regulatory T (eTreg) cells after anti-PD-1 treatment, a higher ratio of T helper-17 (Th17) and T helper-1 cells at baseline, and a higher percentage of Ki-67+ cells among PD-1+CD8+ T cells posttreatment. In clustering analysis using the T-cell parameters, patients with irAEs were grouped into four distinct subtypes: Th17-related, TNF-related, CD8-related Treg-compensated, and CD8-related Treg-uncompensated. The T-cell parameters showed a predictive value for the development of each subtype of severe irAEs. In conclusion, severe irAEs after anti-PD-1 treatment were clustered into four immunological subtypes, and potential biomarkers for early prediction of severe irAEs were proposed.

中文翻译：

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在抗PD-1治疗之前和之后，通过T细胞分析将免疫相关的不良事件分为不同的亚型。

尽管抗程序性死亡1（PD-1）治疗已显示出显着的抗肿瘤功效，但与免疫相关的不良事件（irAEs）仍以异质的临床表现发展。但是，目前对irAE的免疫学理解是有限的。在本研究中，我们分析了从接受抗PD-1治疗的癌症患者获得的外周血T细胞，以确定irAE的免疫学特征。这项研究包括31例难治性胸腺上皮肿瘤（TET）患者参加了pembrolizumab（NCT02607631）的II期临床试验，以及60例接受了pembrolizumab或nivolumab治疗的转移性非小细胞肺癌（NSCLC）患者。通过多色流式细胞术，使用治疗前和抗PD-1抗体首次剂量后7天获得的外周血进行T细胞谱分析。21例TET患者和24例NSCLC患者出现了irAE。7例TET患者（22.6％）和6例NSCLC患者（10.0％）发生严重（≥3级）irAEs。患有严重irAEs的患者在抗PD-1治疗后，效应调节性T（eTreg）细胞的频率显着降低了倍数，基线时T辅助17（Th17）和T辅助1细胞的比例更高，并且PD-1 + CD8 + T细胞后处理中Ki-67 +细胞的比例更高。在使用T细胞参数进行的聚类分析中，患有irAEs的患者分为四个不同的亚型：Th17相关，TNF相关，CD8相关Treg补偿和CD8相关Treg未补偿。T细胞参数显示出对每种严重irAEs亚型发展的预测价值。结论，