Brand, Almut and Singer, Katrin and Koehl, Gudrun E. and Kolitzus, Marlene and Schoenhammer, Gabriele and Thiel, Annette and Matos, Carina and Bruss, Christina and Klobuch, Sebastian and Peter, Katrin and Kastenberger, Michael and Bogdan, Christian and Schleicher, Ulrike and Mackensen, Andreas and Ullrich, Evelyn and Fichtner-Feigl, Stefan and Kesselring, Rebecca and Mack, Matthias and Ritter, Uwe and Schmid, Maximilian and Blank, Christian and Dettmer, Katja and Oefner, Peter J. and Hoffmann, Petra and Walenta, Stefan and Geissler, Edward K. and Pouyssegur, Jacques and Villunger, Andreas and Steven, Andre and Seliger, Barbara and Schreml, Stephan and Haferkamp, Sebastian and Kohl, Elisabeth and Karrer, Sigrid and Berneburg, Mark and Herr, Wolfgang and Mueller-Klieser, Wolfgang and Renner, Kathrin and Kreutz, Marina (2016) LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metabolism, 24 (5). pp. 657-671. ISSN 1550-4131, 1932-7420
Full text not available from this repository. (Request a copy)Abstract
Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha(low)) developed significantly slower than control tumors and showed increased infiltration with IFN-gamma-producing T and NK cells. However, in Rag2(-/-)gamma c(-/-) mice, lacking lymphocytes and NK cells, and in Ifng(-/-) mice, Ldha(low) and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-gamma production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.
Item Type: | Article |
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Uncontrolled Keywords: | LACTATE-DEHYDROGENASE; METASTATIC MELANOMA; INTERFERON-GAMMA; PATIENT SURVIVAL; IMMUNE CELLS; GLYCOLYSIS; CANCER; MICROENVIRONMENT; PROGRESSION; REJECTION; |
Subjects: | 600 Technology > 610 Medical sciences Medicine |
Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Lehrstuhl für Dermatologie und Venerologie Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Immunologie Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Regensburger Centrum für Interventionelle Immunologie (RCI) |
Depositing User: | Dr. Gernot Deinzer |
Date Deposited: | 12 Apr 2019 11:15 |
Last Modified: | 12 Apr 2019 11:19 |
URI: | https://pred.uni-regensburg.de/id/eprint/3959 |
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