Researchers at the Dallas-based UT Southwestern Simmons Cancer Center report that lactate, a metabolic byproduct produced by cells during strenuous exercise, may rejuvenate immune cells that fight cancer. The finding (“Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity”), published in Nature Communications, could eventually be used to develop new strategies to augment the anti-tumor effect of cancer immunotherapies, according to the scientists.

“The lactate that we usually think of as a waste product appears to have a previously unrecognized role in fighting cancer,” said Jinming Gao, PhD, professor of cell biology, otolaryngology-head and neck surgery, and pharmacology.

Researchers at UT Southwestern Simmons Cancer Center found that lactate, a metabolic byproduct produced by cells during strenuous exercise, can rejuvenate immune cells that fight cancer. The image shows single-cell transcriptome analysis enrichment of tumor-infiltrating T cells, the red dots, after lactate treatment. [UT Southwestern Simmons Cancer Center]
“Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis,” the investigators wrote.

“Here we show that lactate is able to increase stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8+ T cell-dependent tumor growth inhibition. Single-cell transcriptomics analysis reveals an increased proportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoral CD3+ cells, a phenotype validated by in vitro lactate treatment of T cells.

“Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice.

“Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.”

Tumor growth significantly reduced in mice treated with lactate

During the study, Gao and his colleagues gave lactate injections to mice with colon cancer or melanoma; other tumor-bearing mice received glucose injections. While glucose had little effect, tumor growth was significantly reduced in mice treated with lactate. When the researchers tried the same experiment in mice genetically engineered to lack T cells, this anti-tumor benefit was blocked, suggesting that lactate appeared to be exerting its effects through this immune cell population.

Administering lactate alone didn’t completely eliminate the tumors. But when the researchers added a commonly used immune checkpoint inhibitor—a type of cancer immunotherapy that releases the brakes that prevent T cells from fighting malignancies—about half of the mice became completely tumor-free. Lactate also significantly improved the effects of a cancer-fighting vaccine and improved the anticancer response of cultured T cells that were injected into tumor-bearing mice.

Further single-cell RNA sequencing analysis showed that more T cells infiltrated the tumors of the lactate-treated mice. Compared to animals that didn’t receive this treatment, T cells from the mice that received lactate expressed more genes associated with stem-like T cells and a smaller number of genes associated with exhaustion markers, making them more fit to effectively fight cancer.

Gao noted that the data suggest that lactate could be used to supplement existing immunotherapies, such as immune checkpoint inhibitors, cancer vaccines, and CAR-T cell therapy. It also suggests that exercise, which naturally raises lactate levels, may be protective against cancer or may augment the immune system to fight cancer as well. Gao and his colleagues plan to investigate these topics in future studies.