Lactic Acid and an Acidic Tumor Microenvironment suppress Anticancer Immunity

Abstract

Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been considered a waste product of this alteration, it is now well accepted that increased lactic acid production and the resultant acidification of the tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, and drug resistance. We and others have hypothesized that excess lactic acid in the TME is responsible for suppressing anticancer immunity. Recent studies support this hypothesis and provide mechanistic evidence explaining how lactic acid and the acidic TME impede immune cell functions. In this review, we consider lactic acid's role as a critical immunoregulatory molecule involved in suppressing immune effector cell proliferation and inducing immune cell de-differentiation. This results in the inhibition of antitumor immune responses and the activation of potent, negative regulators of innate and adaptive immune cells. We also consider the role of an acidic TME in suppressing anticancer immunity. Finally, we provide insights to help translate this new knowledge into impactful anticancer immune therapies.

Keywords: acidic tumor microenvironment; anticancer immunotherapy; cancer-induced immunosuppression; de-differentiation; epigenetic reprograming; lactic acid.

Figure 1

Lactic acid in the tumor microenvironment suppresses the antitumor immune response by negatively regulating innate and adaptive tumor-infiltrating immune cells. First, lactic acid impairs monocyte differentiation into dendritic cells (DCs) and further decreases their antigen-presentation functions. Second, lactic acid inhibits the antitumor activities of immune effector cells, including natural killer and cytotoxic T cells. Lastly, lactic acid promotes the infiltration of immunosuppressive cell types, such as M2 macrophages (M2) -like tumor-associated macrophages, N2 neutrophils (N2)-like tumor-associated neutrophils, myeloid-derived suppressor cells, and regulatory T cells, which can effectively inhibit the antitumor immune response and contribute to cancer immune escape.

Figure 2

The molecular mechanisms by which lactic acid modulates immune cell responses. Lactic acid promotes cancer cell proliferation, drug resistance, and enhanced expression of programmed death-ligand 1 (PD-L1). In addition, lactic acid is responsible for suppressing antitumor immunity. (A) High lactic acid concentrations in the tumor microenvironment disrupts the [H+] gradient between T cells and their environment, reducing monocarboxylate transporter 1 (MCT1)-mediated lactic acid export from T cells. This inhibits effector T cell proliferation. (B) Lactic acid acts as an epigenetic regulator and induces M2 macrophage polarization through epigenetic reprogramming. It directly binds to histone lysine lactylation (Kla) sites (28 of these have been experimentally identified) to direct downstream gene transcription, thereby inducing M2 polarization and enhancing inflammation-independent biological pathways. (C) Lactic acid acts as a signaling molecule. G protein-coupled receptor GPR81 is a lactic acid receptor found on both immune cells and cancer cells. Its activation in cancer cells promotes proliferation, drug resistance, and enhanced expression of PD-L1. Its activation on DCs is associated with decreased levels of cAMP, IL-6, IL-12, and suppressed antigen (Ag) presentation.