Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Cell. 2021 Mar 4;184(5):1281-1298.e26. doi: 10.1016/j.cell.2021.01.022. Epub 2021 Feb 15.
T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.
T 细胞是癌症免疫疗法的关键效应物，但人们对弥漫性神经胶质瘤中 T 细胞的基因表达程序知之甚少。在这里，我们利用单细胞 RNA 测序 (RNA-seq) 绘制了 31 名异柠檬酸脱氢酶 (IDH) 野生型胶质母细胞瘤和 IDH 突变型神经胶质瘤患者肿瘤浸润 T 细胞的基因表达和克隆景观。我们在共表达细胞毒性程序和几种自然杀伤 (NK) 细胞基因的 T 细胞亚群中鉴定出了潜在的抗肿瘤免疫效应物。对克隆扩增的肿瘤浸润 T 细胞的分析进一步确定了 NK 基因 KLRB1（编码 CD161）作为候选抑制受体。因此，KLRB1 的基因失活或抗体介导的 CD161 阻断增强了 T 细胞在体外对神经胶质瘤细胞的杀伤作用及其在体内的抗肿瘤功能。KLRB1 及其相关转录程序也在其他人类癌症的大量 T 细胞群体中表达。我们的工作提供了神经胶质瘤中 T 细胞的图谱，并强调 CD161 和其他 NK 细胞受体作为免疫治疗靶点。
