Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate PMID: 29988124

ADC Targets in Oncology

2026-04-10

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

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].

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.