Tumor-derived lactic acid generates a unique macrophage phenotype.

Abstract

Tumor microenvironment is often characterized with high lactic acid concentration and lactic acid is known to have immunomodulatory effects. In this study, we aim to study the effect of lactic acid on tumor-associated macrophages (TAMs). The TAM phenotype was evaluated in terms of invasion into solid tumor, surface antigen expression, and cytokine secretion profile. To closely mimic the in vivo tumor microenvironment, 3D tumor spheroid model was used, in which monocytes were co-cultured with tumor cells in presence or absence of oxamate, an inhibitor of lactic acid production. We found that lactic acid inhibited monocyte infiltration into tumor spheroid and increased the expression of surface molecules involved in antigen presentation, T cell co-stimulation, and phagocytosis―functions important for antitumor immune response. In addition, lactic acid increased the secretion of pro-inflammatory factors, like IL-6, CXCL10, and G-CSF. These results suggest that lactic acid might promote a pro-inflammatory TAM phenotype with an antitumor potential.