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Bunse, Lukas; Pusch, Stefan; Bunse, Theresa; Sahm, Felix; Sanghvi, Khwab; Friedrich, Mirco; Alansary, Dalia; Sonner, Jana K.; Green, Edward; Deumelandt, Katrin; Kilian, Michael; Neftel, Cyril; Uhlig, Stefanie; Kessler, Tobias; Landenberg, Anna von; Berghoff, Anna S.; Marsh, Kelly; Steadman, Mya; Zhu, Dongwei; Nicolay, Brandon; Wiestler, Benedikt; Breckwoldt, Michael O.; Al-Ali, Ruslan; Karcher-Bausch, Simone; Bozza, Matthias; Özen, Iris; Kramer, Magdalena; Meyer, Jochen; Habel, Antje; Eisel, Jessica; Poschet, Gernot; Weller, Michael; Preusser, Matthias; Nadji-Ohl, Minou; Thon, Niklas; Burger, Michael C.; Harter, Patrick N.; Ratliff, Miriam; Harbottle, Richard; Benner, Axel; Schrimpf, Daniel; Okun, Jürgen; Herold-Mende, Christel; Turcan, Sevin; Kaulfuss, Stefan; Hess-Stumpp, Holger; Bieback, Karen; Cahill, Daniel P.; Plate, Karl H.; Hänggi, Daniel; Dorsch, Marion; Suva, Mario L.; Niemeyer, Barbara A.; Deimling, Andreas von; Wick, Wolfgang; Platten, Michael (2018): Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. In: Nature Medicine, Vol. 24, No. 8: pp. 1192-1203
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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. IDM-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic Mill-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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