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

• DOI: 10.1016/j.cell.2021.01.022
• Publication Date: 2021-02-16T04:23:21Z
• Authors: Nathan D. Mathewson; Orr Ashenberg; Itay Tirosh; Simon Gritsch; Elizabeth M. Perez; Sascha Marx; Livnat Jerby-Arnon; Rony Chanoch-Myers; Toshiro Hara; Alyssa R. Richman; Yoshinaga Ito; Jason Pyrdol; Mirco Friedrich; Kathrin Schumann; Michael J. Poitras; Prafulla C. Gokhale; L. Nicolas Gonzal...; Marni E. Shore; Christine M. Hebert; Brian Shaw; Heather L. Cahill; Matthew Drummond; Wubing Zhang; Olamide Olawoyin; Hiroaki Wakimoto; Orit Rozenblatt-R...; Priscilla K. Bras...; X. Shirley Liu; Pamela S. Jones; Daniel P. Cahill; Matthew P. Frosch; David N. Louis; Gordon J. Freeman; Keith L. Ligon; Alexander Marson; E. Antonio Chiocca; David A. Reardon; Aviv Regev; Mario L. Suvà; Kai W. Wucherpfennig
• Keywords: 0301 basic medicine; T-Lymphocytes; Medical and Health Sciences; Mice; Stem Cell Research - Nonembryonic - Human; T-Lymphocyte Subsets; Lectins; Receptors; Killer Cells; Lymphocytes; Cancer; single-cell RNA-seq; C-Type; Glioma; Biological Sciences; 3. Good health; Killer Cells, Natural; Cell Surface; Natural; Single-Cell Analysis; NK Cell Lectin-Like Receptor Subfamily B; Oncology and Carcinogenesis; Immunology; T cells; Receptors, Cell Surface; Vaccine Related; 03 medical and health sciences; Rare Diseases; Lymphocytes, Tumor-Infiltrating; Antigens, Neoplasm; Genetics; Animals; Lectins, C-Type; Tumor-Infiltrating; IDH-mutant gliomas; Antigens; Biomedical and Clinical Sciences; Animal; Gene Expression Profiling; Human Genome; Neurosciences; glioblastoma; Stem Cell Research; Brain Disorders; Brain Cancer; Disease Models, Animal; Disease Models; Neoplasm; Immunization; Tumor Escape; CD161; Developmental Biology

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.