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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 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.

SUBMITTER: Mathewson ND

PROVIDER: S-EPMC7935772 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Mathewson Nathan D ND Ashenberg Orr O Tirosh Itay I Gritsch Simon S Perez Elizabeth M EM Marx Sascha S Jerby-Arnon Livnat L Chanoch-Myers Rony R Hara Toshiro T Richman Alyssa R AR Ito Yoshinaga Y Pyrdol Jason J Friedrich Mirco M Schumann Kathrin K Poitras Michael J MJ Gokhale Prafulla C PC Gonzalez Castro L Nicolas LN Shore Marni E ME Hebert Christine M CM Shaw Brian B Cahill Heather L HL Drummond Matthew M Zhang Wubing W Olawoyin Olamide O Wakimoto Hiroaki H Rozenblatt-Rosen Orit O Brastianos Priscilla K PK Liu X Shirley XS Jones Pamela S PS Cahill Daniel P DP Frosch Matthew P MP Louis David N DN Freeman Gordon J GJ Ligon Keith L KL Marson Alexander A Chiocca E Antonio EA Reardon David A DA Regev Aviv A Suvà Mario L ML Wucherpfennig Kai W KW

Cell 20210215 5

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 natur ...[more]

PMID: 33592174

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Project description:Our laboratory has recently demonstrated that natural killer (NK) cells are capable of eradicating orthotopically implanted mouse GL26 and rat CNS-1 malignant gliomas soon after intracranial engraftment if the cancer cells are rendered deficient in their expression of the β-galactoside-binding lectin galectin-1 (gal-1). More recent work now shows that a population of Gr-1+/CD11b+ myeloid cells is critical to this effect. To better understand the mechanisms by which NK and myeloid cells cooperate to confer gal-1-deficient tumor rejection we have developed a comprehensive protocol for the isolation and analysis of glioma-infiltrating peripheral blood mononuclear cells (PBMC). The method is demonstrated here by comparing PBMC infiltration into the tumor microenvironment of gal-1-expressing GL26 gliomas with those rendered gal-1-deficient via shRNA knockdown. The protocol begins with a description of how to culture and prepare GL26 cells for inoculation into the syngeneic C57BL/6J mouse brain. It then explains the steps involved in the isolation and flow cytometric analysis of glioma-infiltrating PBMCs from the early brain tumor microenvironment. The method is adaptable to a number of in vivo experimental designs in which temporal data on immune infiltration into the brain is required. The method is sensitive and highly reproducible, as glioma-infiltrating PBMCs can be isolated from intracranial tumors as soon as 24 hr post-tumor engraftment with similar cell counts observed from time point matched tumors throughout independent experiments. A single experimentalist can perform the method from brain harvesting to flow cytometric analysis of glioma-infiltrating PBMCs in roughly 4-6 hr depending on the number of samples to be analyzed. Alternative glioma models and/or cell-specific detection antibodies may also be used at the experimentalists' discretion to assess the infiltration of several other immune cell types of interest without the need for alterations to the overall procedure.

Dataset Information

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

Publications

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

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