美国范德堡大学医学中心Justin M. Balko研究组合作报道了一例检查点抑制剂引起T细胞活化从而导致致命性脑炎的病例。2019年8月，国际知名学术期刊《自然—医学》发表了这一成果。

研究人员报告了一例致转移性黑色素瘤患者在抗程序性细胞死亡受体1治疗期间出现脑炎的致死病例。组织学分析显示强烈的T细胞浸润和明显的程序性死亡配体1表达。研究人员在全球药物警戒数据库（包含多种癌症类型）中确定了与检查点抑制剂方案相关的209例脑炎报告病例，死亡率为19％。研究人员对指示病例和另外两例病例进行了进一步的分析，以揭示这种复发性和暴发性的免疫相关的不良事件（irAE）。空间和多组学分析确定了激活的记忆CD4阳性T细胞在发炎的受影响区域里高度富集。研究人员鉴定了一个高度寡克隆的T细胞受体群，并将其定位到活化的记忆细胞毒性（CD45RO、GZMB、Ki67三阳性）CD4细胞。研究人员还在受影响的区域中鉴定到了Epstein-Barr病毒特异性T细胞受体和EBV阳性淋巴细胞，研究人员推测这些受体在指示病例中有助于神经炎症。总的来说，这里研究的三个案例将CD4阳性和CD8 阳性T细胞鉴定为检查点抑制剂相关免疫脑炎的罪魁祸首。

研究人员表示，检查点抑制剂能够在许多转移性癌症中产生持久的反应，但免疫相关的不良事件（irAE）限制并使其益处复杂化。irAE可以特异性地影响器官系统，其范围从轻度型和自限性到暴发型和致命性。但irAEs的分子机制知之甚少。

附：英文原文

Title: A case report of clonal EBV-like memory CD4 + T cell activation in fatal checkpoint inhibitor-induced encephalitis

Author: Douglas B. Johnson, Wyatt J. McDonnell, Paula I. Gonzalez-Ericsson, Rami N. Al-Rohil, Bret C. Mobley, Joe-Elie Salem, Daniel Y. Wang, Violeta Sanchez, Yu Wang, Cody A. Chastain, Kristi Barker, Yan Liang, Sarah Warren, Joseph M. Beechem, Alexander M. Menzies, Martin Tio, Georgina V. Long, Justine V. Cohen, Amanda C. Guidon, Mabh OHare, Sunandana Chandra, Akansha Chowdhary, Bndicte Lebrun-Vignes, Simone M. Goldinger, Elisabeth J. Rushing, Elizabeth I. Buchbinder, Simon A. Mallal, Chanjuan Shi, Yaomin Xu, Javid J. Moslehi, Melinda E. Sanders, Jeffrey A. Sosman, Justin M. Balko

Issue&Volume: Volume 25 Issue 8, August 2019

Abstract: Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4+ T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45RO+GZMB+Ki67+) CD4 cells. We also identified EpsteinBarr virus-specific T cell receptors and EBV+ lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4+ and CD8+ T cells as culprits of checkpoint inhibitor-associated immune encephalitis.

DOI: 10.1038/s41591-019-0523-2

Source:https://www.nature.com/articles/s41591-019-0523-2