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

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

  • Nat Med. 2018 Aug;24(8):1192-1203. doi: 10.1038/s41591-018-0095-6.
Lukas Bunse 1 2 3 4,  Stefan Pusch 5 6,  Theresa Bunse 1 3 7,  Felix Sahm 5 6,  Khwab Sanghvi 1 4,  Mirco Friedrich 1,  Dalia Alansary 8,  Jana K Sonner 1,  Edward Green 1,  Katrin Deumelandt 1 4,  Michael Kilian 1 4,  Cyril Neftel 9,  Stefanie Uhlig 10,  Tobias Kessler 2 3 11,  Anna von Landenberg 1,  Anna S Berghoff 11 12 13,  Kelly Marsh 14,  Mya Steadman 14,  Dongwei Zhu 14,  Brandon Nicolay 14,  Benedikt Wiestler 15,  Michael O Breckwoldt 1 16,  Ruslan Al-Ali 17,  Simone Karcher-Bausch 1,  Matthias Bozza 18,  Iris Oezen 1,  Magdalena Kramer 1,  Jochen Meyer 5 6,  Antje Habel 5 6,  Jessica Eisel 5 6,  Gernot Poschet 19,  Michael Weller 20,  Matthias Preusser 13 21,  Minou Nadji-Ohl 22,  Niklas Thon 23,  Michael C Burger 24 25,  Patrick N Harter 25 26,  Miriam Ratliff 11 27,  Richard Harbottle 18,  Axel Benner 28,  Daniel Schrimpf 5 6,  Jürgen Okun 29,  Christel Herold-Mende 30,  Sevin Turcan 17,  Stefan Kaulfuss 31,  Holger Hess-Stumpp 31,  Karen Bieback 10,  Daniel P Cahill 32,  Karl H Plate 25 26,  Daniel Hänggi 27,  Marion Dorsch 14,  Mario L Suvà 9,  Barbara A Niemeyer 8,  Andreas von Deimling 4 5,  Wolfgang Wick 2 3 11,  Michael Platten 33 34 35 36
Affiliations

Affiliations

  • 1 German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 2 Department of Neurology, Heidelberg University Medical Center, Heidelberg, Germany.
  • 3 National Center for Tumor Diseases Heidelberg, DKTK, Heidelberg, Germany.
  • 4 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • 5 Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.
  • 6 DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany.
  • 7 Department of Neurology, University Hospital and Medical Faculty Mannheim, Mannheim, Germany.
  • 8 Molecular Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany.
  • 9 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.
  • 10 FlowCore Mannheim and Institute of Transfusion Medicine and Immunology, Mannheim, Germany.
  • 11 DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany.
  • 12 Institute of Neurology, Medical University of Vienna, Vienna, Austria.
  • 13 CNS Tumors Unit, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
  • 14 Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
  • 15 Department of Diagnostic and Interventional Neuroradiology, Neuro-Kopf-Zentrum, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
  • 16 Department of Neuroradiology, Heidelberg University Medical Center, Heidelberg, Germany.
  • 17 Max Eder Junior Group on Low Grade Gliomas, Heidelberg University Medical Center, Heidelberg, Germany.
  • 18 DNA Vectors Unit, DKFZ, Heidelberg, Germany.
  • 19 Center for Organismal Studies, University Heidelberg, Heidelberg, Germany.
  • 20 Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
  • 21 Department for Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.
  • 22 Department of Neurosurgery, Stuttgart Clinics, Stuttgart, Germany.
  • 23 Department of Neurosurgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
  • 24 Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany.
  • 25 DKTK Partner Site Frankfurt/Mainz, Frankfurt, Germany.
  • 26 Institute of Neurology (Edinger Institute), University Hospital and Medical Faculty, Goethe University, Frankfurt, Germany.
  • 27 Neurosurgery Clinic, University Hospital Mannheim, Mannheim, Germany.
  • 28 Division of Biostatistics, DKFZ, Heidelberg, Germany.
  • 29 Metabolic Center Heidelberg, University Children's Hospital, Heidelberg, Germany.
  • 30 Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Medical Center, Heidelberg, Germany.
  • 31 Research and Development, Pharmaceuticals, Bayer AG, Berlin, Germany.
  • 32 Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 33 German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
  • 34 Department of Neurology, Heidelberg University Medical Center, Heidelberg, Germany. [email protected].
  • 35 National Center for Tumor Diseases Heidelberg, DKTK, Heidelberg, Germany. [email protected].
  • 36 Department of Neurology, University Hospital and Medical Faculty Mannheim, Mannheim, Germany. [email protected].
PMID: 29988124 DOI: 10.1038/s41591-018-0095-6
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.

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