LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells

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 (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Cell Metabolism Elsevier (Cell Press)

Book Volume: 24

Pages Range: 657-671

Journal Issue: 5

DOI: 10.1016/j.cmet.2016.08.011

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-?-producing T and NK cells. However, in Rag2(-/-)?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-? 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.

Authors with CRIS profile

Christian Bogdan Lehrstuhl für Mikrobiologie und Infektionsimmunologie Ulrike Schleicher Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Andreas Mackensen Lehrstuhl für Innere Medizin V

Involved external institutions

Universitätsklinikum Regensburg DE Germany (DE) Universität Regensburg DE Germany (DE) Antoni van Leeuwenhoek NL Netherlands (NL) Johannes Gutenberg-Universität Mainz (JGU) DE Germany (DE) University of Nice Sophia Antipolis / Université Nice Sophia Antipolis FR France (FR) Medizinische Universität Innsbruck AT Austria (AT) Martin-Luther-Universität Halle-Wittenberg (MLU) DE Germany (DE)

How to cite

APA:

Brand, A., Singer, K., Koehl, G.E., Kolitzus, M., Schoenhammer, G., Thiel, A.,... Kreutz, M. (2016). LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metabolism, 24(5), 657-671. https://doi.org/10.1016/j.cmet.2016.08.011

MLA:

Brand, Almut, et al. "LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells." Cell Metabolism 24.5 (2016): 657-671.

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