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

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Details zur Publikation

Autorinnen und Autoren: 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
Zeitschrift: Cell Metabolism
Jahr der Veröffentlichung: 2016
Band: 24
Heftnummer: 5
Seitenbereich: 657-671
ISSN: 1550-4131


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.



FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Bogdan, Christian Prof. Dr.
Lehrstuhl für Mikrobiologie und Infektionsimmunologie
Mackensen, Andreas Prof. Dr.
Lehrstuhl für Innere Medizin V
Schleicher, Ulrike PD Dr.
Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene


Einrichtungen weiterer Autorinnen und Autoren

Antoni van Leeuwenhoek
Johannes Gutenberg-Universität Mainz
Martin-Luther-Universität Halle-Wittenberg (MLU)
Medizinische Universität Innsbruck
Universität Regensburg
Universitätsklinikum Regensburg
University of Nice Sophia Antipolis / Université Nice Sophia Antipolis


Zitierweisen

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://dx.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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Zuletzt aktualisiert 2018-10-10 um 02:23