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

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

  • Bunse L German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Pusch S Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.
  • Bunse T German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Sahm F Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.
  • Sanghvi K German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 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.
  • Kilian M German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 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.
  • 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.
  • 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.
  • 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.
  • Habel A Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.
  • Eisel J Department of Neuropathology, Heidelberg University Medical Center, 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.
  • 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.
  • Harter PN DKTK Partner Site Frankfurt/Mainz, Frankfurt, Germany.
  • Ratliff M DKTK CCU Neurooncology, DKFZ, Heidelberg, 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.
  • 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.
  • 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.
  • Wick W Department of Neurology, Heidelberg University Medical Center, 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.
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  • 2018-07-11
Published in:
  • Nature medicine. - 2018
Adenosine Triphosphate
Animals
Apoptosis
Brain Neoplasms
Calcium
Cell Line, Tumor
Cell Proliferation
Glioma
Glutarates
Humans
Immunity
Isocitrate Dehydrogenase
Lymphocyte Activation
Mice, Inbred C57BL
Mutation
NFATC Transcription Factors
Paracrine Communication
Polyamines
RNA, Messenger
Receptors, Antigen, T-Cell
Signal Transduction
T-Lymphocytes
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/266727
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