Cell
Volume 184, Issue 5, 4 March 2021, Pages 1281-1298.e26
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Article
Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis

https://doi.org/10.1016/j.cell.2021.01.022Get rights and content
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Highlights

  • Single-cell analysis charts expression, clonal landscape of glioma-infiltrating T cells

  • T cells with a cytotoxicity program express multiple NK cell receptors

  • The NK cell receptor CD161 inhibits killing of glioma cells by T cells

  • Tumor cells and immunosuppressive myeloid cells express the CLEC2D ligand

Summary

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

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These authors contributed equally

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These authors contributed equally

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