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

Cell Metab. 2016 Nov 8;24(5):657-671. doi: 10.1016/j.cmet.2016.08.011. Epub 2016 Sep 15.


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.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Count
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Survival / immunology
  • Cytokines / biosynthesis
  • Glycolysis / drug effects
  • Humans
  • Immunologic Surveillance* / drug effects
  • Interferon-gamma / pharmacology
  • Isoenzymes / metabolism
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • L-Lactate Dehydrogenase / metabolism*
  • Lactate Dehydrogenase 5
  • Lactic Acid / biosynthesis*
  • Lactic Acid / pharmacology
  • Male
  • Melanoma / immunology*
  • Melanoma / pathology
  • Mice, Inbred C57BL
  • NFATC Transcription Factors / metabolism
  • Phenotype
  • Sodium Lactate / pharmacology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Up-Regulation / drug effects


  • Cytokines
  • Isoenzymes
  • NFATC Transcription Factors
  • Lactic Acid
  • Interferon-gamma
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5
  • Sodium Lactate