Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurological Surgery, Emory University School of Medicine, Atlanta, GA, USA.
Cell Rep Med. 2022 May 17;3(5):100620. doi: 10.1016/j.xcrm.2022.100620. Epub 2022 Apr 27.
Metastatic disease in the brain is difficult to control and predicts poor prognosis. Here, we analyze human brain metastases and demonstrate their robust infiltration by CD8 T cell subsets with distinct antigen specificities, phenotypic states, and spatial localization within the tumor microenvironment. Brain metastases are densely infiltrated by T cells; the majority of infiltrating CD8 T cells express PD-1. Single-cell RNA sequencing shows significant clonal overlap between proliferating and exhausted CD8 T cells, but these subsets have minimal clonal overlap with circulating and other tumor-infiltrating CD8 T cells, including bystander CD8 T cells specific for microbial antigens. Using spatial transcriptomics and spatial T cell receptor (TCR) sequencing, we show these clonally unrelated, phenotypically distinct CD8 T cell populations occupy discrete niches within the brain metastasis tumor microenvironment. Together, our work identifies signaling pathways within CD8 T cells and in their surrounding environment that may be targeted for immunotherapy of brain metastases.
脑转移瘤难以控制，且预示着预后不良。在这里，我们分析了人类脑转移瘤，并证实其被具有不同抗原特异性、表型状态和空间定位的 CD8 T 细胞亚群强烈浸润。脑转移瘤被 T 细胞密集浸润；大多数浸润的 CD8 T 细胞表达 PD-1。单细胞 RNA 测序显示增殖和耗竭的 CD8 T 细胞之间存在显著的克隆重叠，但这些亚群与循环和其他肿瘤浸润的 CD8 T 细胞（包括针对微生物抗原的旁观者 CD8 T 细胞）的克隆重叠最小。使用空间转录组学和空间 T 细胞受体（TCR）测序，我们表明这些克隆上无关、表型上不同的 CD8 T 细胞群体在脑转移瘤肿瘤微环境中占据离散的龛位。总之，我们的工作确定了 CD8 T 细胞及其周围环境中的信号通路，这些通路可能成为脑转移瘤免疫治疗的靶点。
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