Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
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Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. / 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; von Landenberg, Anna; Berghoff, Anna S; Marsh, Kelly; Steadman, Mya; Zhu, Dongwei; Nicolay, Brandon; Wiestler, Benedikt; Breckwoldt, Michael O; Al-Ali, Ruslan; Karcher-Bausch, Simone; Bozza, Matthias; Oezen, 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; Suvà, Mario L; Niemeyer, Barbara A; von Deimling, Andreas; Wick, Wolfgang; Platten, Michael.
in: NAT MED, Jahrgang 24, Nr. 8, 08.2018, S. 1192-1203.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
AU - Bunse, Lukas
AU - Pusch, Stefan
AU - Bunse, Theresa
AU - Sahm, Felix
AU - Sanghvi, Khwab
AU - Friedrich, Mirco
AU - Alansary, Dalia
AU - Sonner, Jana K
AU - Green, Edward
AU - Deumelandt, Katrin
AU - Kilian, Michael
AU - Neftel, Cyril
AU - Uhlig, Stefanie
AU - Kessler, Tobias
AU - von Landenberg, Anna
AU - Berghoff, Anna S
AU - Marsh, Kelly
AU - Steadman, Mya
AU - Zhu, Dongwei
AU - Nicolay, Brandon
AU - Wiestler, Benedikt
AU - Breckwoldt, Michael O
AU - Al-Ali, Ruslan
AU - Karcher-Bausch, Simone
AU - Bozza, Matthias
AU - Oezen, Iris
AU - Kramer, Magdalena
AU - Meyer, Jochen
AU - Habel, Antje
AU - Eisel, Jessica
AU - Poschet, Gernot
AU - Weller, Michael
AU - Preusser, Matthias
AU - Nadji-Ohl, Minou
AU - Thon, Niklas
AU - Burger, Michael C
AU - Harter, Patrick N
AU - Ratliff, Miriam
AU - Harbottle, Richard
AU - Benner, Axel
AU - Schrimpf, Daniel
AU - Okun, Jürgen
AU - Herold-Mende, Christel
AU - Turcan, Sevin
AU - Kaulfuss, Stefan
AU - Hess-Stumpp, Holger
AU - Bieback, Karen
AU - Cahill, Daniel P
AU - Plate, Karl H
AU - Hänggi, Daniel
AU - Dorsch, Marion
AU - Suvà, Mario L
AU - Niemeyer, Barbara A
AU - von Deimling, Andreas
AU - Wick, Wolfgang
AU - Platten, Michael
PY - 2018/8
Y1 - 2018/8
N2 - 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.
AB - 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.
KW - Adenosine Triphosphate/metabolism
KW - Animals
KW - Apoptosis
KW - Brain Neoplasms/genetics
KW - Calcium/metabolism
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Glioma/genetics
KW - Glutarates/metabolism
KW - Humans
KW - Immunity
KW - Isocitrate Dehydrogenase/genetics
KW - Lymphocyte Activation/immunology
KW - Mice, Inbred C57BL
KW - Mutation/genetics
KW - NFATC Transcription Factors/metabolism
KW - Paracrine Communication
KW - Polyamines/metabolism
KW - RNA, Messenger/genetics
KW - Receptors, Antigen, T-Cell/metabolism
KW - Signal Transduction
KW - T-Lymphocytes/immunology
U2 - 10.1038/s41591-018-0095-6
DO - 10.1038/s41591-018-0095-6
M3 - SCORING: Journal article
C2 - 29988124
VL - 24
SP - 1192
EP - 1203
JO - NAT MED
JF - NAT MED
SN - 1078-8956
IS - 8
ER -