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

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 Gonzalez Castro, Marni E. Shore, Christine M. Hebert, Brian ShawHeather L. Cahill, Matthew Drummond, Wubing Zhang, Olamide Olawoyin, Hiroaki Wakimoto, Orit Rozenblatt-Rosen, Priscilla K. Brastianos, 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

Research output: Contribution to journalArticlepeer-review

200 Scopus citations


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. Single-cell analysis of tumor-infiltrating T cells in glioma patients identifies a T cell population co-expressing a cytotoxicity program and NK cell receptors. Mathewson et al. reveal the functional significance of NK cell receptors such as CD161 in inhibiting the anti-tumor function of T cells, highlighting their potential as targets for immunotherapy.

Original languageEnglish
Pages (from-to)1281-1298.e26
Issue number5
StatePublished - 4 Mar 2021
Externally publishedYes


  • CD161
  • IDH-mutant gliomas
  • T cells
  • glioblastoma
  • single-cell RNA-seq


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