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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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.
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 firstname.lastname@example.org.
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