动态细胞因子特征预测肺癌中严重免疫相关性肝炎使用PD-1/PD-L1阻断治疗的生存结果。
Dynamic cytokines signature predicts survival outcome from severe Immune-related hepatitis with PD-1/PD-L1 blockade in lung cancer.
发表日期：2023 Aug 28
作者：
Liang Zeng, Yuling Zhou, Qinqin Xu, Zhe Huang, Lianxi Song, Zhan Wang, Li Deng, Yongsheng Wu, Yanchao Liang, Zhentian Liu, Xuan Gao, Xin Yi, Qiongzhi He, Xuefeng Xia, Haiyan Yang, Xing Zhang, Huan Yan, Haoyue Qin, Shaoding Lin, Nong Yang, Yongchang Zhang
来源：
LUNG CANCER
摘要：
免疫相关不良事件（irAEs），尤其是免疫检查点抑制剂（ICI）治疗引起的免疫相关肝炎（IRH），是一种潜在严重的并发症。本回顾性队列研究旨在调查IRH的潜在预后和预测生物标志物。该研究纳入了接受ICI治疗的37例晚期肺癌患者，并将其分为两组：≥3级（G3）IRH组（n = 17）和无irAE组（n = 20）。采集三个不同时间点的血液样本和治疗前肿瘤活检样本，使用多组学分析法进行分析。与无irAE组相比，≥G3-IRH组的IL-1B RNA表达显著增加（limma，倍数=1.94）。与无irAE组相比，≥G3-IRH组的单核细胞和嗜酸粒细胞浸润增加，巨噬细胞浸润降低，特别是巨噬细胞M2型。治疗前肿瘤样本的转录组学分析显示，≥G3-IRH组的多个与炎症相关的基因明显上调（假发现率<0.05）。此外，≥G3-IRH组的各种促炎因子和趋化因子在血浆中明显降低。≥G3-IRH组的亚组分析显示，与IRH相关死亡患者相比，IRH缓解者的血浆IL-1A显著升高。死亡患者的免疫评分和从IRH发病第七天到基线的欧氏距离增加更大，在免疫抑制后欧氏距离显著增加，提示免疫状态过度刺激。我们的研究证明了IL-1B过表达与IRH易感性的关联。炎症细胞因子的免疫评分和欧氏距离可能对≥G3 IRH的生存预后具有预测价值。版权所有©2023 Elsevier B.V. 保留所有权利。
Immune-related adverse events (irAEs), particularly immune-related hepatitis (IRH) is a potentially serious complication of immune checkpoint inhibitor (ICI) therapy. This retrospective cohort study investigated potential prognostic and predictive biomarkers for IRH.This study included 37 patients with advanced lung cancer who received ICIs and were divided into two groups: ≥Grade 3 (G3)-IRH group (n = 17) and without irAE (no-irAE) group (n = 20). Blood samples collected at three different time points and pre-treatment tumor biopsy samples were analyzed using multi-omics assays.The IL-1B RNA expression was significantly increased (limma, fold = 1.94) in the ≥ G3-IRH group than the no-irAE group. Compared with no-irAE group, ≥G3-IRH group had higher monocyte and eosinophil infiltration and lower macrophage infiltration, particularly macrophage M2. Transcriptomics analyses of pre-treatment tumor samples revealed significant upregulation of various inflammation-related genes in the ≥ G3-IRH group (False discovery rate < 0.05). Moreover, various proinflammatory cytokines and chemokines were significantly lower in the plasma of the ≥ G3-IRH group than in the no-irAE group. Subgroup analyses of the ≥ G3-IRH group revealed that plasma IL-1A was significantly higher among those whose IRH resolved than those who had IRH-related death. Patients who died had a greater increase in immune score and Euclidean distance from the baseline to the seventh day of IRH onset, with a dramatic increase in Euclidean distance after immunosuppression, suggesting overstimulated immune status.Our study demonstrated the association between IL-1B overexpression and IRH susceptibility. Immune score and Euclidean distance of inflammatory cytokines may provide predictive value on the survival outcome from ≥ G3 IRH.Copyright © 2023 Elsevier B.V. All rights reserved.