PDF(Pubmed)
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 Epstein-Barr 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.
摘要：
检查点抑制剂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）复杂化并限制其获益。IrAE可以特异性地影响器官系统;表现范围从轻度和自我限制到暴发性和致命性。对irAE的分子机制知之甚少。这里,我们报道一例转移性黑色素瘤患者在抗程序性细胞死亡受体1治疗过程中出现脑炎的致命性病例.组织学分析显示T细胞浸润和明显的程序性死亡配体1表达。我们在全球药物警戒数据库（多种癌症类型）中确定了209例与检查点抑制剂方案相关的脑炎报告病例。死亡率为19%。我们对索引病例和另外两个病例进行了进一步分析，以阐明这种复发性和暴发性irAE。空间和多维分析确定活化的记忆CD4+T细胞高度富集在发炎的，受影响地区。我们确定了一个高度寡克隆的T细胞受体库，我们定位于激活的记忆细胞毒性(CD45RO+GZMB+Ki67+)CD4细胞。我们还在受影响的区域中鉴定了EB病毒特异性T细胞受体和EBV淋巴细胞，我们推测在索引病例中导致神经炎症。总的来说，本文研究的3例病例将CD4+和CD8+T细胞确定为检查点抑制剂相关性免疫性脑炎的罪魁祸首.
