Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate.

Autor: Bunse L; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Neurology, Heidelberg University Medical Center, Heidelberg, Germany.; National Center for Tumor Diseases Heidelberg, DKTK, Heidelberg, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., Pusch S; Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.; DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany., Bunse T; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; National Center for Tumor Diseases Heidelberg, DKTK, Heidelberg, Germany.; Department of Neurology, University Hospital and Medical Faculty Mannheim, Mannheim, Germany., Sahm F; Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.; DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany., Sanghvi K; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., Friedrich M; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Alansary D; Molecular Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany., Sonner JK; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Green E; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Deumelandt K; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., Kilian M; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., Neftel C; Broad Institute of Harvard and MIT and Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Uhlig S; FlowCore Mannheim and Institute of Transfusion Medicine and Immunology, Mannheim, Germany., Kessler T; Department of Neurology, Heidelberg University Medical Center, Heidelberg, Germany.; National Center for Tumor Diseases Heidelberg, DKTK, Heidelberg, Germany.; DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany., von Landenberg A; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Berghoff AS; DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany.; Institute of Neurology, Medical University of Vienna, Vienna, Austria.; CNS Tumors Unit, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Marsh K; Agios Pharmaceuticals, Inc., Cambridge, MA, USA., Steadman M; Agios Pharmaceuticals, Inc., Cambridge, MA, USA., Zhu D; Agios Pharmaceuticals, Inc., Cambridge, MA, USA., Nicolay B; Agios Pharmaceuticals, Inc., Cambridge, MA, USA., Wiestler B; Department of Diagnostic and Interventional Neuroradiology, Neuro-Kopf-Zentrum, Klinikum rechts der Isar, Technical University Munich, Munich, Germany., Breckwoldt MO; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Neuroradiology, Heidelberg University Medical Center, Heidelberg, Germany., Al-Ali R; Max Eder Junior Group on Low Grade Gliomas, Heidelberg University Medical Center, Heidelberg, Germany., Karcher-Bausch S; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Bozza M; DNA Vectors Unit, DKFZ, Heidelberg, Germany., Oezen I; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Kramer M; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Meyer J; Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.; DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany., Habel A; Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.; DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany., Eisel J; Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.; DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany., Poschet G; Center for Organismal Studies, University Heidelberg, Heidelberg, Germany., Weller M; Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland., Preusser M; CNS Tumors Unit, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; Department for Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria., Nadji-Ohl M; Department of Neurosurgery, Stuttgart Clinics, Stuttgart, Germany., Thon N; Department of Neurosurgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany., Burger MC; Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany.; DKTK Partner Site Frankfurt/Mainz, Frankfurt, Germany., Harter PN; DKTK Partner Site Frankfurt/Mainz, Frankfurt, Germany.; Institute of Neurology (Edinger Institute), University Hospital and Medical Faculty, Goethe University, Frankfurt, Germany., Ratliff M; DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany.; Neurosurgery Clinic, University Hospital Mannheim, Mannheim, Germany., Harbottle R; DNA Vectors Unit, DKFZ, Heidelberg, Germany., Benner A; Division of Biostatistics, DKFZ, Heidelberg, Germany., Schrimpf D; Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.; DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany., Okun J; Metabolic Center Heidelberg, University Children's Hospital, Heidelberg, Germany., Herold-Mende C; Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Medical Center, Heidelberg, Germany., Turcan S; Max Eder Junior Group on Low Grade Gliomas, Heidelberg University Medical Center, Heidelberg, Germany., Kaulfuss S; Research and Development, Pharmaceuticals, Bayer AG, Berlin, Germany., Hess-Stumpp H; Research and Development, Pharmaceuticals, Bayer AG, Berlin, Germany., Bieback K; FlowCore Mannheim and Institute of Transfusion Medicine and Immunology, Mannheim, Germany., Cahill DP; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Plate KH; DKTK Partner Site Frankfurt/Mainz, Frankfurt, Germany.; Institute of Neurology (Edinger Institute), University Hospital and Medical Faculty, Goethe University, Frankfurt, Germany., Hänggi D; Neurosurgery Clinic, University Hospital Mannheim, Mannheim, Germany., Dorsch M; Agios Pharmaceuticals, Inc., Cambridge, MA, USA., Suvà ML; Broad Institute of Harvard and MIT and Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Niemeyer BA; Molecular Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany., von Deimling A; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.; Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany., Wick W; Department of Neurology, Heidelberg University Medical Center, Heidelberg, Germany.; National Center for Tumor Diseases Heidelberg, DKTK, Heidelberg, Germany.; DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany., Platten M; German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.platten@dkfz.de.; Department of Neurology, Heidelberg University Medical Center, Heidelberg, Germany. m.platten@dkfz.de.; National Center for Tumor Diseases Heidelberg, DKTK, Heidelberg, Germany. m.platten@dkfz.de.; Department of Neurology, University Hospital and Medical Faculty Mannheim, Mannheim, Germany. m.platten@dkfz.de.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2018 Aug; Vol. 24 (8), pp. 1192-1203. Date of Electronic Publication: 2018 Jul 09.
DOI: 10.1038/s41591-018-0095-6
Abstrakt: The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell-derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.
Databáze: MEDLINE
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