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

Publication date: Available online 15 September 2016
Source:Cell Metabolism
Author(s): Almut Brand, Katrin Singer, Gudrun E. Koehl, Marlene Kolitzus, Gabriele Schoenhammer, Annette Thiel, Carina Matos, Christina Bruss, Sebastian Klobuch, Katrin Peter, Michael Kastenberger, Christian Bogdan, Ulrike Schleicher, Andreas Mackensen, Evelyn Ullrich, Stefan Fichtner-Feigl, Rebecca Kesselring, Matthias Mack, Uwe Ritter, Maximilian Schmid, Christian Blank, Katja Dettmer, Peter J. Oefner, Petra Hoffmann, Stefan Walenta, Edward K. Geissler, Jacques Pouyssegur, Andreas Villunger, André Steven, Barbara Seliger, Stephan Schreml, Sebastian Haferkamp, Elisabeth Kohl, Sigrid Karrer, Mark Berneburg, Wolfgang Herr, Wolfgang Mueller-Klieser, Kathrin Renner, Marina Kreutz
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 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.

Graphical abstract

Teaser

Brand et al. link altered tumor glucose metabolism and immune escape and show that increased lactic acid production by LDHA in cancer cells impairs cytokine production, in particular IFN-γ, in tumor-infiltrating T cells and NK cells, thereby inhibiting tumor immunosurveillance and promoting tumor growth.


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