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

Lukas Bunse; Stefan Pusch; Theresa Bunse; Felix Sahm; Khwab Sanghvi; Mirco Friedrich; Dalia Alansary; Jana K Sonner; Edward Green; Katrin Deumelandt; Michael Kilian; Cyril Neftel; Stefanie Uhlig; Tobias Kessler; Anna von Landenberg; Anna S Berghoff; Kelly Marsh; Mya Steadman; Dongwei Zhu; Brandon Nicolay; Benedikt Wiestler; Michael O Breckwoldt; Ruslan Al-Ali; Simone Karcher-Bausch; Matthias Bozza; Iris Oezen; Magdalena Kramer; Jochen Meyer; Antje Habel; Jessica Eisel; Gernot Poschet; Michael Weller; Matthias Preusser; Minou Nadji-Ohl; Niklas Thon; Michael C Burger; Patrick N Harter; Miriam Ratliff; Richard Harbottle; Axel Benner; Daniel Schrimpf; Jürgen Okun; Christel Herold-Mende; Sevin Turcan; Stefan Kaulfuss; Holger Hess-Stumpp; Karen Bieback; Daniel P Cahill; Karl H Plate; Daniel Hänggi; Marion Dorsch; Mario L Suvà; Barbara A Niemeyer; Andreas von Deimling; Wolfgang Wick; Michael Platten

doi:10.1038/s41591-018-0095-6

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. Epub 2018 Jul 9.

Authors

Lukas Bunse^{1

2

3

4}, Stefan Pusch^{5

6}, Theresa Bunse^{1

3

7}, Felix Sahm^{5

6}, Khwab Sanghvi^{1

4}, Mirco Friedrich¹, Dalia Alansary⁸, Jana K Sonner¹, Edward Green¹, Katrin Deumelandt^{1

4}, Michael Kilian^{1

4}, Cyril Neftel⁹, Stefanie Uhlig¹⁰, Tobias Kessler^{2

3

11}, Anna von Landenberg¹, Anna S Berghoff^{11

12

13}, Kelly Marsh¹⁴, Mya Steadman¹⁴, Dongwei Zhu¹⁴, Brandon Nicolay¹⁴, Benedikt Wiestler¹⁵, Michael O Breckwoldt^{1

16}, Ruslan Al-Ali¹⁷, Simone Karcher-Bausch¹, Matthias Bozza¹⁸, Iris Oezen¹, Magdalena Kramer¹, Jochen Meyer^{5

6}, Antje Habel^{5

6}, Jessica Eisel^{5

6}, Gernot Poschet¹⁹, Michael Weller²⁰, Matthias Preusser^{13

21}, Minou Nadji-Ohl²², Niklas Thon²³, Michael C Burger^{24

25}, Patrick N Harter^{25

26}, Miriam Ratliff^{11

27}, Richard Harbottle¹⁸, Axel Benner²⁸, Daniel Schrimpf^{5

6}, Jürgen Okun²⁹, Christel Herold-Mende³⁰, Sevin Turcan¹⁷, Stefan Kaulfuss³¹, Holger Hess-Stumpp³¹, Karen Bieback¹⁰, Daniel P Cahill³², Karl H Plate^{25

26}, Daniel Hänggi²⁷, Marion Dorsch¹⁴, Mario L Suvà⁹, Barbara A Niemeyer⁸, Andreas von Deimling^{4

5}, Wolfgang Wick^{2

3

11}, Michael Platten^{33

34

35

36}

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. 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Animals
Apoptosis
Brain Neoplasms / genetics
Brain Neoplasms / immunology
Calcium / metabolism
Cell Line, Tumor
Cell Proliferation
Glioma / genetics
Glioma / immunology
Glutarates / metabolism*
Humans
Immunity*
Isocitrate Dehydrogenase / genetics
Isocitrate Dehydrogenase / metabolism
Lymphocyte Activation / immunology
Mice, Inbred C57BL
Mutation / genetics
NFATC Transcription Factors / metabolism
Paracrine Communication
Polyamines / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Antigen, T-Cell / metabolism
Signal Transduction
T-Lymphocytes / immunology*

Substances

Glutarates
NFATC Transcription Factors
Polyamines
RNA, Messenger
Receptors, Antigen, T-Cell
alpha-hydroxyglutarate
Adenosine Triphosphate
Isocitrate Dehydrogenase
IDH1 protein, human
Calcium