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

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.

• Authors: 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
• Journal: Nature medicine (Nat Med) Vol. 24 Issue 8 Pg. 1192-1203 (08 2018) ISSN: 1546-170X [Electronic] United States
• PMID: 29988124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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