| Autor: |
Wolfgang Mueller-Klieser, Evelyn Ullrich, E. K. Geissler, Andreas Villunger, Almut Brand, Sigrid Karrer, Kathrin Renner, André Steven, Peter J. Oefner, Stefan Walenta, Elisabeth Kohl, Annette Thiel, Christian U. Blank, Gudrun E. Koehl, Jacques Pouysségur, Sebastian Haferkamp, Maximilian Schmid, Marina Kreutz, Carina Matos, Stefan Fichtner-Feigl, Katja Dettmer, Petra Hoffmann, Ulrike Schleicher, Sebastian Klobuch, Barbara Seliger, Katrin Singer, Michael Kastenberger, Christian Bogdan, Matthias Mack, Mark Berneburg, K. Peter, Stephan Schreml, Uwe Ritter, Wolfgang Herr, Marlene Kolitzus, Andreas Mackensen, Christina Bruss, Rebecca Kesselring, Gabriele Schoenhammer |
| Rok vydání: |
2016 |
| Předmět: |
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| Zdroj: |
Cell Metabolism. 24:657-671 |
| ISSN: |
1550-4131 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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