Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?
Bottom Line: 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.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.This paradigm shift can have major impact on therapeutic strategy development.
Affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.Show MeSH
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Mentions: The primary cause responsible for the acidic pH and pH-dependent T-cell function-suppressive effect in a tumour micro-environment has been identified as lactic acid 26–30. It has also been demonstrated that cancer-generated lactic acid and the resultant acidification of the micro-environment increase the expression of ARG1 in tumour-associated macrophages, characteristic of the M2 helper phenotype 31. Furthermore, another study showed that under physiological or slightly alkaline conditions, glycolysis was selectively up-regulated by neuroblastoma cells, whereas oxidative phosphorylation was preferred by the cells when the extracellular pH was acidic; these effects were independent of changes in oxygen concentration or glucose supply 32. Thus, aerobic glycolysis can serve as a negative feedback loop that adjusts the pericellular pH in tumours towards a broad acidic range by increased lactic acid production and secretion. Taken together, the studies suggest that cancer cells can enhance their survival by inhibiting the anti-cancer immune response through actively maintaining a slightly acidic micro-environment. They apparently can do this by altering their energy metabolism to regulate their lactic acid production/secretion 32. The locally suppressed immunity then serves as a basis for the establishment of the malignancy and its subsequent malignant progression (see Figure 1).
Affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.