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

Abstract

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) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2γc mice, lacking lymphocytes and NK cells, and in Ifng mice, Ldha 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.

Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma

“…While tumor cells can deplete nutrients (10,15,24,34), no decrease in interstitial glucose levels was observed in ccRCC tumors relative to adjacent normal kidney tissue ( Figure 3A). Nevertheless, lactate can inhibit T cell function (11,35) and was increased in ccRCC interstitial fluid. ccRCC CD8 TIL had normal or a trend toward increased expression of glucose transporter Glut1 and hexokinase 2 (HK2) ( Figure 3B).…”

“…In addition, consumption of nutrients by cancer cells may limit T cell access to glucose and key amino acids needed for T cell activation and effector signaling pathways (10,24,25). Tumor cell production of lactic acid can also suppress T cell signaling through NFAT and IFN-γ secretion to impair antitumor immunity (11). Tumor infiltrating lymphocytes (TIL) have been reported to lose mitochondrial mass in a melanoma model, rendering T cells unable to efficiently meet bioenergetic needs (26).…”

“…One potential barrier to T cell-mediated elimination of cancer cells is the requirement of lymphocytes to undergo metabolic reprogramming and induce high rates of aerobic glycolysis for effector function (9)(10)(11). Resting T cells utilize a catabolic and largely oxidative metabolism that promotes survival and quiescence.…”

Aneustat (OMN54) has aerobic glycolysis‐inhibitory activity and also immunomodulatory activity as indicated by a first‐generation PDX prostate cancer model

“…aerobic glycolysis, which is commonly used by cancer cells, leads to increased lactic acid secretion and a subsequent low, immune function‐inhibiting pH in their environment 7, 8. The acidification of the tumor microenvironment can suppress the host anticancer immune response as it has been found to promote expansion of intratumoral numbers of Treg cells and MDSCs and reduce intratumoral levels of CD8 + T cells and NK cells,9, 10 resulting in a lower ratio of intratumoral CD8 + T cells to Treg cells as observed in cancers of patients 11. Such a role of cancer‐generated lactic acid has been demonstrated using B16 mouse melanoma allografts in immunocompetent C57BL/6 and Rag2 −/− mice.…”

“…Such a role of cancer‐generated lactic acid has been demonstrated using B16 mouse melanoma allografts in immunocompetent C57BL/6 and Rag2 −/− mice. Thus a reduction of lactic acid secretion by the tumors, obtained by specific depletion of lactate dehydrogenase‐A (LDHA), led to lower numbers of intratumoral MDSCs and higher numbers of intratumoral NK cells and CD8 + T cells compared to controls 10. As such, targeting aerobic glycolysis to reduce lactic acid secretion by cancer cells appears to be a useful strategy for restoring the host anticancer immune response 7, 8.…”