Targeting Lactate in TME

Acidic condition is one of the most significant characteristics of the tumor microenvironment (TME). The Warburg effect increases the conversion of glucose to lactate in relation to low oxidative profile due to aerobic glycolysis in tumor cells. High lactate concentrations are produced by tumor cells and excreted by monocarboxylate transporters (MCT) from tumor cells at high rates, shaping acidic TME. As a matter of fact, high lactate production remodels the TME by contributing to acidosis, acting as a cancer cell metabolic fuel and inducing immunosuppression resulting in aggressive proliferation, invasion, migration and resistance therapy. Because of lactate's emerging and critical role, targeting lactate production and its transporters is important for preventing and managing tumorigenesis.

Role of Lactate In TME

• Metabolic substrate

Lactate can be incorporated into the tricarboxylic acid (TCA) cycle and be a source of energy. Hypoxic TME results in the metabolic symbiosis between hypoxic and normoxic compartments of the tumor. Lactate products produced by hypoxic cells can be used as a metabolic fuel by normoxic cells through oxidative phosphorylation

• Lactate effect on tumor-infiltrating immune cells

Apart from their direct starvation effect, lactate also inhibits immune cells function and induces immunosuppressive TME. The production of lactate in tumor cells impacts interferon-gamma production by tumor-infiltrating T cells, NK activation, and the proportion of myeloid-derived suppressor cells. High concentrations of lactic acid in the TME block lactic acid export by T cells, thereby disturbing their metabolism and function. Furthermore, lactate derived from tumors induces M2-like polarization of tumor-associated macrophages (TAMs) via induction of HIF-1α targets VEGF and arginase, further dampening antitumor immunity.

• Lactate and tumor metastasis

The acidic condition increases the expression of proangiogenic factors IL-8 and VEGF and stimulates angiogenesis, both important involved in cancer metastasis. Besides lactate accumulation in the primary tumor site, its immunosuppressive properties can outspread to distant sites, thus stimulating invasion and metastasis in a paracrine fashion.

Fig.1 Impact of lactate on TME. (Romero-Garcia, 2016)

Strategies of Targeting Lactate Metabolism

Due to the multitude of effects of lactate in promoting immune evasion of tumors and stimulating tumor angiogenesis, targeting lactate metabolism in combination with immunotherapy is a promising approach to enhance the efficacy of immune therapies. Now some drugs targeting lactate to treat tumors are being developed. Strategies that decrease lactate accumulation either through inhibiting lactate-producing enzyme lactate dehydrogenase (LDH), inhibiting the lactate transporters MCT1/4, or neutralizing lactic acid-induced acidity (oral bicarbonate supplementation) have proved effective at improving anti-tumor immune cells.

Reference

1. Romero-Garcia, Susana, et al. "Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance." Frontiers in immunology 7 (2016): 52. Distributed under Open Access license CC BY 4.0, without modification.