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

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Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis
Cell ( IF 45.5 ) Pub Date : 2021-02-15 , DOI: 10.1016/j.cell.2021.01.022
Nathan D Mathewson ₁ , Orr Ashenberg ₂ , Itay Tirosh ₃ , Simon Gritsch ₄ , Elizabeth M Perez ₅ , Sascha Marx ₆ , Livnat Jerby-Arnon ₇ , Rony Chanoch-Myers ₃ , Toshiro Hara ₄ , Alyssa R Richman ₄ , Yoshinaga Ito ₆ , Jason Pyrdol ₈ , Mirco Friedrich ₈ , Kathrin Schumann ₉ , Michael J Poitras ₁₀ , Prafulla C Gokhale ₁₀ , L Nicolas Gonzalez Castro ₁₁ , Marni E Shore ₄ , Christine M Hebert ₄ , Brian Shaw ₁₂ , Heather L Cahill ₁₃ , Matthew Drummond ₁₃ , Wubing Zhang ₁₄ , Olamide Olawoyin ₈ , Hiroaki Wakimoto ₁₅ , Orit Rozenblatt-Rosen ₁₆ , Priscilla K Brastianos ₁₂ , X Shirley Liu ₁₄ , Pamela S Jones ₁₅ , Daniel P Cahill ₁₅ , Matthew P Frosch ₁₃ , David N Louis ₁₃ , Gordon J Freeman ₁₇ , Keith L Ligon ₁₈ , Alexander Marson ₁₉ , E Antonio Chiocca ₂₀ , David A Reardon ₂₁ , Aviv Regev ₂₂ , Mario L Suvà ₄ , Kai W Wucherpfennig ₁

Affiliation

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.
Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel.
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.
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.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, 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 Genetics, Stanford University School of Medicine, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
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.
Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
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.
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.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
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.
Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, 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; Genentech, South San Francisco, CA, USA; Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA 02139, USA.

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.

中文翻译：

通过单细胞分析在神经胶质瘤浸润 T 细胞中鉴定出抑制性 CD161 受体

T 细胞是癌症免疫疗法的关键效应器，但人们对其在弥漫性神经胶质瘤中的基因表达程序知之甚少。在这里，我们利用单细胞 RNA 测序 (RNA-seq) 绘制了 31 名异柠檬酸脱氢酶 (IDH) 野生型胶质母细胞瘤和 IDH 突变型胶质瘤患者肿瘤浸润 T 细胞的基因表达和克隆图谱。我们在共表达细胞毒性程序和几种自然杀伤 (NK) 细胞基因的 T 细胞亚群中鉴定出抗肿瘤免疫的潜在效应因子。对克隆扩增的肿瘤浸润 T 细胞的分析进一步确定 NK 基因KLRB1 （编码 CD161）是候选抑制性受体。因此， KLRB1的基因失活或抗体介导的 CD161 阻断可增强 T 细胞介导的体外杀伤神经胶质瘤细胞及其体内抗肿瘤功能。 KLRB1及其相关转录程序也在其他人类癌症中的大量 T 细胞群中表达。我们的工作提供了神经胶质瘤中 T 细胞的图谱，并强调 CD161 和其他 NK 细胞受体作为免疫治疗靶点。

更新日期：2021-03-04

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