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

Nature Medicine volume 24, pages 1192–1203 (2018)Cite this article

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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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Fig. 1: T cells are paracrine targets of R-2-HG.
Fig. 2: R-2-HG directly impairs activation of T cells.
Fig. 3: Differential expression profile of intratumoral T cells associates with IDH1 status.
Fig. 4: R-2-HG interferes with calcium-dependent transcriptional activity of NFAT.
Fig. 5: R-2-HG inhibits ATP-dependent TCR signaling and polyamine biosynthesis in T cells.
Fig. 6: R-2-HG impairs T cell antitumor immunity.

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Acknowledgements

We acknowledge the support of the DKFZ Light Microscopy Facility, the microarray unit of the DKFZ Genomics and Proteomics Core Facility, the Transgenic Service of the Center for Preclinical Research, DKFZ, and the DKFZ–Bayer Alliance. We thank the Metabolomics Core Technology Platform of the Excellence Cluster CellNetworks for support with UPLC-based metabolite quantification. The results published here are in part based on data generated by the TCGA Research Network: http://cancergenome.nih.gov/. A2DR1 mice were provided by Institute Pasteur. We thank S. Kircher for flow cytometric analyses; H.Y. Ngyuen, L. Dörner, K. Rauschenbach, and M. Fischer for technical support; and J. Jung for graphics design. This work was supported by the epigenetics@dkfz program to L.B., the DKFZ-MOST program (project number 2526) and the Helmholtz Program Immunology and Inflammation, the Dr. Rolf M. Schwiete Foundation and the German Research Foundation (DFG) (FOR2289: PL315/3-1), the Sonderförderlinie ‘Neuroinflammation’ of the Ministry of Science of Baden Württemberg and the German Ministry of Education and Science (National Center for Tumor Diseases Heidelberg NCT 3.0 program ‘Precision immunotherapy of brain tumors’ and the DKTK program) to M.Pl. the Joint Funding Program MGH-Heidelberg Alliance in Neuro-Oncology to M.Pl. and M.S., the Wilhelm Sander Foundation (2012.118.1) and the German Cancer Aid (70112399) to M.Pl. and A.v.D., the German Cancer Aid (110624) to W.W., the ZUK 49/2 from the DFG to G.P., FOR2289 to B.A.N. and D.A., SFB894 to B.A.N., and the German Cancer Aid to S.T.. L.B. and M.F. are members of the MD/PhD program at Heidelberg University. L.B. was funded by Heidelberg Medical Faculty. T.B., K.S., J.K.S., and M.Ki. are supported by the Helmholtz International Graduate School, T.B. is supported by the Medical Faculty and University Hospital Mannheim. F.S. is supported by a postdoctoral fellowship of the University Hospital Heidelberg. B.W. is supported by the Faculty of Medicine of the Technical University of Munich (KKF grant). E.G. is supported by a Marie-Curie fellowship.

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Author notes

  1. These authors contributed equally: Lukas Bunse, Stefan Pusch, Theresa Bunse.

Authors and Affiliations

  1. German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Lukas Bunse, Theresa Bunse, Khwab Sanghvi, Mirco Friedrich, Jana K. Sonner, Edward Green, Katrin Deumelandt, Michael Kilian, Anna von Landenberg, Michael O. Breckwoldt, Simone Karcher-Bausch, Iris Oezen, Magdalena Kramer & Michael Platten

  2. Department of Neurology, Heidelberg University Medical Center, Heidelberg, Germany

    Lukas Bunse, Tobias Kessler, Wolfgang Wick & Michael Platten

  3. National Center for Tumor Diseases Heidelberg, DKTK, Heidelberg, Germany

    Lukas Bunse, Theresa Bunse, Tobias Kessler, Wolfgang Wick & Michael Platten

  4. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany

    Lukas Bunse, Khwab Sanghvi, Katrin Deumelandt, Michael Kilian & Andreas von Deimling

  5. Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany

    Stefan Pusch, Felix Sahm, Jochen Meyer, Antje Habel, Jessica Eisel, Daniel Schrimpf & Andreas von Deimling

  6. DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany

    Stefan Pusch, Felix Sahm, Jochen Meyer, Antje Habel, Jessica Eisel & Daniel Schrimpf

  7. Department of Neurology, University Hospital and Medical Faculty Mannheim, Mannheim, Germany

    Theresa Bunse & Michael Platten

  8. Molecular Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany

    Dalia Alansary & Barbara A. Niemeyer

  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

    Cyril Neftel & Mario L. Suvà

  10. FlowCore Mannheim and Institute of Transfusion Medicine and Immunology, Mannheim, Germany

    Stefanie Uhlig & Karen Bieback

  11. DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany

    Tobias Kessler, Anna S. Berghoff, Miriam Ratliff & Wolfgang Wick

  12. Institute of Neurology, Medical University of Vienna, Vienna, Austria

    Anna S. Berghoff

  13. CNS Tumors Unit, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

    Anna S. Berghoff & Matthias Preusser

  14. Agios Pharmaceuticals, Inc., Cambridge, MA, USA

    Kelly Marsh, Mya Steadman, Dongwei Zhu, Brandon Nicolay & Marion Dorsch

  15. Department of Diagnostic and Interventional Neuroradiology, Neuro-Kopf-Zentrum, Klinikum rechts der Isar, Technical University Munich, Munich, Germany

    Benedikt Wiestler

  16. Department of Neuroradiology, Heidelberg University Medical Center, Heidelberg, Germany

    Michael O. Breckwoldt

  17. Max Eder Junior Group on Low Grade Gliomas, Heidelberg University Medical Center, Heidelberg, Germany

    Ruslan Al-Ali & Sevin Turcan

  18. DNA Vectors Unit, DKFZ, Heidelberg, Germany

    Matthias Bozza & Richard Harbottle

  19. Center for Organismal Studies, University Heidelberg, Heidelberg, Germany

    Gernot Poschet

  20. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland

    Michael Weller

  21. Department for Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria

    Matthias Preusser

  22. Department of Neurosurgery, Stuttgart Clinics, Stuttgart, Germany

    Minou Nadji-Ohl

  23. Department of Neurosurgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany

    Niklas Thon

  24. Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany

    Michael C. Burger

  25. DKTK Partner Site Frankfurt/Mainz, Frankfurt, Germany

    Michael C. Burger, Patrick N. Harter & Karl H. Plate

  26. Institute of Neurology (Edinger Institute), University Hospital and Medical Faculty, Goethe University, Frankfurt, Germany

    Patrick N. Harter & Karl H. Plate

  27. Neurosurgery Clinic, University Hospital Mannheim, Mannheim, Germany

    Miriam Ratliff & Daniel Hänggi

  28. Division of Biostatistics, DKFZ, Heidelberg, Germany

    Axel Benner

  29. Metabolic Center Heidelberg, University Children’s Hospital, Heidelberg, Germany

    Jürgen Okun

  30. Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Medical Center, Heidelberg, Germany

    Christel Herold-Mende

  31. Research and Development, Pharmaceuticals, Bayer AG, Berlin, Germany

    Stefan Kaulfuss & Holger Hess‐Stumpp

  32. Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Daniel P. Cahill

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Contributions

L.B., S.P., and T.B. designed and performed experiments, analyzed data, and wrote the paper. F.S. and A.v.D. provided glioma tissue, determined IDH1 status, provided tissue stainings, and performed 850 k methylation arrays. K.S., M.F., M.Ki., A.v.L., and S.K.-B. performed in vitro experiments. J.K.S., M.Kr., and I.O. performed in vivo experiments. D.A. and B.A.N. performed calcium and respiration measurements. E.G., M.B., and R.H. performed genetic modification of cell lines. K.D. analyzed primary human tissue. C.N., M.L.S., S.U., and K.B. were involved in TIL processing. T.K. and D.S. analyzed RNA-seq data. A.S.B. and M.Pr. provided glioma tissue, determined IDH1 status, and provided immunohistochemistry stainings. K.M., M.S., D.Z., B.N., and M.D. performed metabolomics and interpreted data. B.W. performed statistical and TCGA analyses. M.O.B. performed magnetic resonance imaging. R.A.-A. and S.T. performed epigenetic profiling. J.M. and A.H. performed RNA-seq. G.P. performed adenosine phosphate and polyamine measurements. M.W. provided glioma tissues and was involved in data interpretation. M.N.-O., N.T., M.C.B., P.N.H., M.R., D.P.C., K.H.P., and D.H. provided glioma tissue. A.B. performed KEGG pathway analyses. J.E. and J.O. performed R-2-HG measurements. C.H.-M. provided the primary glioma cell line. S.K. and H.H.-S. interpreted data and provided BAY1436032. W.W. was involved in study design and data interpretation. M.Pl. conceptualized the study, interpreted data, and wrote the paper.

Corresponding author

Correspondence to Michael Platten.

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Competing interests

M.Pl., W.W., and T.B. are inventors on a patent application entitled ‘Means and methods for treating or diagnosing IDH1R132H mutant-positive cancers’ (WO 2013/102641 A1, PCT/EP2013/050048). S.P. and A.v.D. are eligible to royalties as co-inventors of BAY 1436032 and are patent holders of ‘Means and methods for the determination of (D)-2-hydroxyglutarate (D2HG)’ (WO2013127997A1). This patent is under the administrative supervision of the DKFZ technology transfer office. K.M., M.S., D.Z., B.N., and M.D. are full-time employees of Agios. S.K. and H.H.S. are full-time employees of Bayer. The other authors declare no conflict of interest. Requests for materials should be addressed to m.platten@dkfz.de.

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Bunse, L., Pusch, S., Bunse, T. et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med 24, 1192–1203 (2018). https://doi.org/10.1038/s41591-018-0095-6

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