[PDF][PDF] LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells

A Brand, K Singer, GE Koehl, M Kolitzus… - Cell metabolism, 2016 - cell.com
A Brand, K Singer, GE Koehl, M Kolitzus, G Schoenhammer, A Thiel, C Matos, C Bruss…
Cell metabolism, 2016cell.com
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-γ-producing T and NK cells. However, in
Rag2–/–γc–/–mice, lacking lymphocytes and NK cells, and in Ifng–/–mice, Ldha low and …
Summary
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.
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