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Nat Med. 2018 Aug;24(8):1192-1203. doi: 10.1038/s41591-018-0095-6. Epub 2018 Jul 9.

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

Author information

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. m.platten@dkfz.de.
34
Department of Neurology, Heidelberg University Medical Center, Heidelberg, Germany. m.platten@dkfz.de.
35
National Center for Tumor Diseases Heidelberg, DKTK, Heidelberg, Germany. m.platten@dkfz.de.
36
Department of Neurology, University Hospital and Medical Faculty Mannheim, Mannheim, Germany. m.platten@dkfz.de.

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.

PMID:
29988124
DOI:
10.1038/s41591-018-0095-6
[Indexed for MEDLINE]

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