| Literature DB >> 27641098 |
Almut Brand1, Katrin Singer1, Gudrun E Koehl2, Marlene Kolitzus1, Gabriele Schoenhammer1, Annette Thiel1, Carina Matos1, Christina Bruss1, Sebastian Klobuch1, Katrin Peter3, Michael Kastenberger1, Christian Bogdan4, Ulrike Schleicher4, Andreas Mackensen5, Evelyn Ullrich6, Stefan Fichtner-Feigl7, Rebecca Kesselring2, Matthias Mack8, Uwe Ritter9, Maximilian Schmid10, Christian Blank11, Katja Dettmer12, Peter J Oefner12, Petra Hoffmann3, Stefan Walenta13, Edward K Geissler2, Jacques Pouyssegur14, Andreas Villunger15, André Steven16, Barbara Seliger16, Stephan Schreml17, Sebastian Haferkamp17, Elisabeth Kohl17, Sigrid Karrer17, Mark Berneburg17, Wolfgang Herr1, Wolfgang Mueller-Klieser13, Kathrin Renner3, Marina Kreutz18.
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 (Ldhalow) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2-/-γc-/- mice, lacking lymphocytes and NK cells, and in Ifng-/- mice, Ldhalow 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-γ 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.Entities:
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Year: 2016 PMID： 27641098 DOI： 10.1016/j.cmet.2016.08.011
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287