LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells
- Brand, A.
- Singer, K.
- Koehl, G. E.
- Kolitzus, M.
- Schoenhammer, G.
- Thiel, A.
- Matos, C.
- Bruss, C.
- Klobuch, S.
- Peter, K.
- Kastenberger, M.
- Bogdan, C.
- Schleicher, U.
- Mackensen, Andreas
- Ullrich, E.
- Fichtner-Feigl, S.
- Kesselring, R.
- Mack, M.
- Ritter, U.
- Schmid, M.
- Blank, C.
- Dettmer, Katja
- Oefner, Peter J.
- Hoffmann, P.
- Walenta, S.
- Geissler, E. K.
- Pouyssegur, J.
- Villunger, A.
- Steven, A.
- Seliger, B.
- Schreml, S.
- Haferkamp, S.
- Kohl, E.
- Karrer, S.
- Berneburg, Mark
- Herr, Wolfgang
- Mueller-Klieser, W.
- Renner, K.
- Kreutz, Marina
DOIAbstract
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 diminish...
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