IDH mutations in the interplay of metabolism and antileikemic immune response

• Applicants: Professor Dr. Wolfgang Herr; Professorin Dr. Marina P. Kreutz, since 9/2014; Professorin Dr. Simone Thomas
• Subject Area: Hematology, Oncology
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190230491

• Final Report Year: 2019

Final Report Abstract

Our results show that IDH mutation associated D-2-HG secretion triggers paracrine effects resulting in a block of differentiation and activation of DCs in the tumor environment. Interestingly, not only the classical oncometabolute D-2-HG but also its enantiomer L-2-HG had immunomodulatory potential and reprogrammed DC metabolism and function. Furthermore our data suggest that abundantly produced D-2HG in tumors that harbor IDH mutations such as AML and glioma may act as a novel immunometabolic modulator of T cells. The T-cells’ bioenergetics are shifted towards oxidative phosphorylation and interference with the stability of the pro-glycolytic HIF-1α diminishes the formation of pro-inflammatory Th17 cells and favors the abundance of Tregs.

Publications

• (2016) LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab. Nov 8;24(5):657-671
  Brand, Almut; Singer, Katrin; Koehl, Gudrun E.; Kolitzus, Marlene; Schoenhammer, Gabriele; Thiel, Annette; Matos, Carina; Bruss, Christina; Klobuch, Sebastian; Peter, Katrin; Kastenberger, Michael; Bogdan, Christian; Schleicher, Ulrike; Mackensen, Andreas; Ullrich, Evelyn; Fichtner-Feigl, Stefan; Kesselring, Rebecca; Mack, Matthias; Ritter, Uwe; ... & Kreutz, Marina
  
• (2017). Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment. Front Immunol. Mar 8;8:248
  Renner, Kathrin; Singer, Katrin; Koehl, Gudrun E.; Geissler, Edward K.; Peter, Katrin; Siska, Peter J. & Kreutz, Marina
  
• (2018) Combined Metabolic Targeting With Metformin and the NSAIDs Diflunisal and Diclofenac Induces Apoptosis in Acute Myeloid Leukemia Cells. Front Pharmacol. 2018 Nov 2;9:1258
  Renner, Kathrin; Seilbeck, Anton; Kauer, Nathalie; Ugele, Ines; Siska, Peter J.; Brummer, Christina; Bruss, Christina; Decking, Sonja-Maria; Fante, Matthias; Schmidt, Astrid; Hammon, Kathrin; Singer, Katrin; Klobuch, Sebastian; Thomas, Simone; Gottfried, Eva; Peter, Katrin & Kreutz, Marina
  
• (2018). Tumor immunoevasion via acidosis dependent induction of regulatory tumor-associated macrophages. Nat Immunol. Dec; 19(12):1319-1329
  Bohn, Toszka; Rapp, Steffen; Luther, Natascha; Klein, Matthias; Bruehl, Till-Julius; Kojima, Nobuhiko; Aranda Lopez, Pamela; Hahlbrock, Jennifer; Muth, Sabine; Endo, Shogo; Pektor, Stefanie; Brand, Almut; Renner, Kathrin; Popp, Vanessa; Gerlach, Katharina; Vogel, Dennis; Lueckel, Christina; Arnold-Schild, Danielle; Pouyssegur, Jacques; ... & Bopp, Tobias
  
• D-2-hydroxyglutarate interferes with HIF-1a stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization. Oncoimmunol 2018; 7:e1445454
  Böttcher, Martin; Renner, Kathrin; Berger, Raffaela; Mentz, Kristin; Thomas, Simone; Cardenas-Conejo, Zugey Elizabeth; Dettmer, Katja; Oefner, Peter J.; Mackensen, Andreas; Kreutz, Marina & Mougiakakos, Dimitrios
  
• (2019). D-2-Hydroxyglutarate and L-2- Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells. Int J Mol Sci. Feb 10;20(3)
  Ugele, Ines; Cárdenas-Conejo, Zugey Elizabeth; Hammon, Kathrin; Wehrstein, Monika; Bruss, Christina; Peter, Katrin; Singer, Katrin; Gottfried, Eva; Boesch, Jakob; Oefner, Peter; Dettmer, Katja; Renner, Kathrin & Kreutz, Marina