Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate.
| Title: | Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. |
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| Authors: | 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. |
| Source: | Nature medicine [Nat Med] 2018 Aug; Vol. 24 (8), pp. 1192-1203. Date of Electronic Publication: 2018 Jul 09. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE |
| Imprint Name(s): | Publication: New York Ny : Nature Publishing Company; Original Publication: New York, NY : Nature Pub. Co., [1995- |
| MeSH Terms: | Immunity*; Glutarates/*metabolism ; T-Lymphocytes/*immunology; Adenosine Triphosphate/metabolism ; Brain Neoplasms/genetics ; Brain Neoplasms/immunology ; Calcium/metabolism ; Glioma/genetics ; Glioma/immunology ; Isocitrate Dehydrogenase/genetics ; Isocitrate Dehydrogenase/metabolism ; Lymphocyte Activation/immunology ; Mutation/genetics ; NFATC Transcription Factors/metabolism ; Polyamines/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Animals ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Mice, Inbred C57BL ; Paracrine Communication ; Signal Transduction |
| Abstract: | 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. |
| Comments: | Comment in: Haematologica. 2024 Aug 01;109(8):2500-2514. doi: 10.3324/haematol.2023.283597.. (PMID: 38235501) |
| Substance Nomenclature: | 0 (Glutarates); 0 (NFATC Transcription Factors); 0 (Polyamines); 0 (RNA, Messenger); 0 (Receptors, Antigen, T-Cell); 2889-31-8 (alpha-hydroxyglutarate); 8L70Q75FXE (Adenosine Triphosphate); EC 1.1.1.41 (Isocitrate Dehydrogenase); EC 1.1.1.42. (IDH1 protein, human); SY7Q814VUP (Calcium) |
| Entry Date(s): | Date Created: 20180711 Date Completed: 20190510 Latest Revision: 20240819 |
| Update Code: | 20260130 |
| DOI: | 10.1038/s41591-018-0095-6 |
| PMID: | 29988124 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't