Using scRNAseq of isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) and IDH mutant glioma, Mathewson et al. detected cytolytic T cells expressing an NK cell signature, with greater abundance in GBM and among clonally expanded or PD-1lo T cells. CD8+ and CD4+ GBM-infiltrating T cells expressed CD161 (encoded by KLRB1), an inhibitor of NK cell lytic activity. CD161’s ligand, CLEC2D, was expressed by CD45+ immune and glioma cells. Anti-CD161 antibody or gRNA editing of KLRB1 boosted T cell lysis of patient-derived gliomaspheres and antitumor activity in humanized mouse models. The KLRB1 profile was also detected in T cells infiltrating other cancers.
Contributed by Paula Hochman
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.
Author Info: (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 Ne
Author Info: (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 Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel. (9) 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. (10) 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. (11) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (12) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (13) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (14) Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitt Mnchen (TUM), Munich, Germany. (15) Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (16) Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (17) 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. (18) 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. (19) 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. (20) 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. (21) Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (22) Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (23) Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (24) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (25) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA. (26) 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. (27) 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. (28) Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (29) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA. (30) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA. (31) Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (32) Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (33) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (34) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (35) 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. (36) Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA. (37) 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. (38) 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. (39) 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. (40) 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.
