Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis

Abstract

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 Tcells 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 Tcells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating Tcells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances Tcell-mediated killing of glioma cells invitro and their anti-tumor function invivo. KLRB1 and its associated transcriptional program are also expressed by substantial Tcell populations in other human cancers. Our work provides an atlas of Tcells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.