Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?

Abstract

The common preference of cancers for lactic acid-generating metabolic energy pathways has led to proposals that their reprogrammed metabolism confers growth advantages such as decreased susceptibility to hypoxic stress. Recent observations, however, suggest that it generates a novel way for cancer survival. There is increasing evidence that cancers can escape immune destruction by suppressing the anti-cancer immune response through maintaining a relatively low pH in their micro-environment. Tumours achieve this by regulating lactic acid secretion via modification of glucose/glutamine metabolisms. We propose that the maintenance by cancers of a relatively low pH in their micro-environment, via regulation of their lactic acid secretion through selective modification of their energy metabolism, is another major mechanism by which cancers can suppress the anti-cancer immune response. Cancer-generated lactic acid could thus be viewed as a critical, immunosuppressive metabolite in the tumour micro-environment rather than a 'waste product'. This paradigm shift can have major impact on therapeutic strategy development.

Keywords: Warburg effect; aerobic glycolysis; glutaminolysis; immune suppression; lactic acid; tumour micro-environment.

Figure 1

A proposed model for the central, regulatory immunosuppressive role of cancer-generated lactic acid with both experimentally demonstrated (in black) and potential (in grey) consequences. The excess lactic acid produced by cancer cells through reprogrammed metabolism results in an acidified tumour micro-environment. This decrease in pH promotes multiple cancer processes, including angiogenesis, invasion, and metastasis. More importantly, the acidic tumour micro-environment also suppresses the anti-cancer immune response, particularly through decreased cytotoxic T-cell function, reduced dendritic cell maturation, and enhanced helper cell activities. This locally suppressed immunity then enables cancer cells to survive and serves as a basis for subsequent malignant progression. As such, cancer-generated lactic acid promotes tumour evasion of immune destruction and should be viewed as a critical immunosuppressive metabolite rather than a ‘waste product’.