1. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
- Author
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Iris Oezen, Michael Kilian, Michael O. Breckwoldt, Mario L. Suvà, Michael C. Burger, Mirco Friedrich, Khwab Sanghvi, Karl H. Plate, Magdalena Kramer, Sevin Turcan, Daniel Hänggi, Niklas Thon, Daniel Schrimpf, Stefan Kaulfuss, Katrin Deumelandt, Jochen Meyer, Richard Harbottle, Jürgen G. Okun, Theresa Bunse, Edward W. Green, Tobias Kessler, Miriam Ratliff, Michael Platten, Jana K. Sonner, Brandon Nicolay, Marion Dorsch, Michael Weller, Anna von Landenberg, Ruslan Al-Ali, Mya Steadman, Matthias Bozza, Holger Hess-Stumpp, Karen Bieback, Dongwei Zhu, Stefan Pusch, Cyril Neftel, Wolfgang Wick, Jessica Eisel, Benedikt Wiestler, Antje Habel, Minou Nadji-Ohl, Axel Benner, Christel Herold-Mende, Anna S. Berghoff, Dalia Alansary, Patrick N. Harter, Lukas Bunse, Kelly Marsh, Gernot Poschet, Barbara A. Niemeyer, Andreas von Deimling, Daniel P. Cahill, Felix Sahm, Simone Karcher-Bausch, Matthias Preusser, and Stefanie Uhlig
- Subjects
0301 basic medicine ,T-Lymphocytes ,T cell ,Receptors, Antigen, T-Cell ,Apoptosis ,Lymphocyte Activation ,General Biochemistry, Genetics and Molecular Biology ,Glutarates ,03 medical and health sciences ,Adenosine Triphosphate ,Antigen ,Cell Line, Tumor ,Paracrine Communication ,Histone methylation ,Polyamines ,medicine ,Animals ,Humans ,RNA, Messenger ,Cell Proliferation ,NFATC Transcription Factors ,Brain Neoplasms ,Chemistry ,Cell growth ,Immunity ,Glioma ,General Medicine ,Isocitrate Dehydrogenase ,Mice, Inbred C57BL ,030104 developmental biology ,Isocitrate dehydrogenase ,medicine.anatomical_structure ,Cell culture ,Mutation ,Cancer research ,Calcium ,Signal transduction ,Signal Transduction - 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.
- Published
- 2018
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