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

Cell. 2021 Mar 4;184(5):1281-1298.e26. doi: 10.1016/j.cell.2021.01.022. Epub 2021 Feb 15.

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 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.

Keywords: CD161; IDH-mutant gliomas; T cells; glioblastoma; single-cell RNA-seq.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Neoplasm
  • Disease Models, Animal
  • Gene Expression Profiling
  • Glioma / genetics
  • Glioma / immunology*
  • Killer Cells, Natural / immunology
  • Lectins, C-Type / genetics
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • NK Cell Lectin-Like Receptor Subfamily B / genetics*
  • Receptors, Cell Surface / genetics
  • Single-Cell Analysis
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • Tumor Escape

Substances

  • Antigens, Neoplasm
  • CLEC2D protein, human
  • KLRB1 protein, human
  • Lectins, C-Type
  • NK Cell Lectin-Like Receptor Subfamily B
  • Receptors, Cell Surface