作者
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,J. Meyer,Antje Habel,Jessica Eisel,Gernot Poschet,Michael Weller,Minou Nadji-Ohl,Niklas Thon,Michael C. Burger,Patrick N. Harter,Miriam Ratliff,Richard P. Harbottle,Axel Benner,Daniel Schrimpf,Jürgen G. Okun,Christel Herold‐Mende,Şevin 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
摘要
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.