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 A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, Kastenberger M, Bogdan C, Schleicher U, Mackensen A, Ullrich E, Fichtner-Feigl S, Kesselring R, Mack M, Ritter U, Schmid M, Blank C, Dettmer K, Oefner PJ, Hoffmann P, Walenta S, Geissler EK, Pouyssegur J, Villunger A, Steven A, Seliger B, Schreml S, Haferkamp S, Kohl E, Karrer S, Berneburg M, Herr W, Mueller-Klieser W, Renner K, Kreutz M
  
• (2017). Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment. Front Immunol. Mar 8;8:248
  Renner K, Singer K, Koehl GE, Geissler EK, Peter K, Siska PJ, Kreutz M
  
• (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 K, Seilbeck A, Kauer N, Ugele I, Siska PJ, Brummer C, Bruss C, Decking SM, Fante M, Schmidt A, Hammon K, Singer K, Klobuch S, Thomas S, Gottfried E, Peter K, Kreutz M
  
• (2018). Tumor immunoevasion via acidosis dependent induction of regulatory tumor-associated macrophages. Nat Immunol. Dec; 19(12):1319-1329
  Bohn T., Rapp S., Luther N., Klein M., Bruehl T., Kojima N Lopez P:A., Hahlbrock J., Muth S., Endo S., Pektor S., Brand A., Renner K., Popp V., Gerlach K., Vogel D., Lueckel C., Arnold-Schild D., Pouyssegur J., Kreutz M., Huber M., KoenigJ., Weigmann B., Probst H., Stebut E., Becker C., Schild H., Schmitt E., Bopp T
  
• D-2-hydroxyglutarate interferes with HIF-1a stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization. Oncoimmunol 2018; 7:e1445454
  Böttcher M, Renner K, Berger R, Mentz K, Thomas S, Zugey E, Dettmer K, Oefner PJ, Mackensen A, Kreutz M, Mougiakakos D
  
• (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 I, Cárdenas-Conejo ZE, Hammon K, Wehrstein M, Bruss C, Peter K, Singer K, Gottfried E, Boesch J, Oefner P, Dettmer K, Renner K, Kreutz M