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 Shaw; Heather 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

doi:10.1016/j.cell.2021.01.022

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.

Authors

Nathan D Mathewson¹, Orr Ashenberg², Itay Tirosh³, Simon Gritsch⁴, Elizabeth M Perez⁵, Sascha Marx⁶, Livnat Jerby-Arnon⁷, Rony Chanoch-Myers³, Toshiro Hara⁴, Alyssa R Richman⁴, Yoshinaga Ito⁶, Jason Pyrdol⁸, Mirco Friedrich⁸, Kathrin Schumann⁹, Michael J Poitras¹⁰, Prafulla C Gokhale¹⁰, L Nicolas Gonzalez Castro¹¹, Marni E Shore⁴, Christine M Hebert⁴, Brian Shaw¹², Heather L Cahill¹³, Matthew Drummond¹³, Wubing Zhang¹⁴, Olamide Olawoyin⁸, Hiroaki Wakimoto¹⁵, Orit Rozenblatt-Rosen¹⁶, Priscilla K Brastianos¹², X Shirley Liu¹⁴, Pamela S Jones¹⁵, Daniel P Cahill¹⁵, Matthew P Frosch¹³, David N Louis¹³, Gordon J Freeman¹⁷, Keith L Ligon¹⁸, Alexander Marson¹⁹, E Antonio Chiocca²⁰, David A Reardon²¹, Aviv Regev²², Mario L Suvà²³, Kai W Wucherpfennig²⁴

Affiliations

¹ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
⁶ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁸ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁹ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), Munich, Germany.
¹⁰ Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
¹¹ Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹² Departments of Neurology and Radiation Oncology, Divisions of Hematology/Oncology and Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
¹³ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁵ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Genentech, South San Francisco, CA, USA.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁸ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
¹⁹ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
²⁰ Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.
²¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: david_reardon@dfci.harvard.edu.
²² Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Genentech, South San Francisco, CA, USA; Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA 02139, USA. Electronic address: aregev@broadinstitute.org.
²³ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Electronic address: suva.mario@mgh.harvard.edu.
²⁴ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: kai_wucherpfennig@dfci.harvard.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding