Cellular 'waste product' helps immune cells to fight cancer

Scientists from the University of Texas Southwestern Medical Center have found that lactate, a metabolic by-product produced by cells during strenuous exercise, can rejuvenate immune cells that fight cancer. Their finding, published in the journal Nature Communications, could eventually be used to develop new strategies to augment the anti-tumour effect of cancer immunotherapies.

Lactate is commonly used in Ringer’s solution, administered intravenously to replace fluids after blood loss (due to trauma, surgery or severe burns) or to treat a condition called metabolic acidosis. While lactic acid (lactate with an additional proton) has been associated with cancer growth and immune suppression, the effects of lactate on cancer and immunity have been unclear.

To investigate this question, Dr Jimmy Gao and his colleagues gave lactate injections to mice with colon cancer or melanoma; other tumour-bearing mice received glucose injections. While glucose had little effect, tumour 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-tumour 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 tumours. 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 the mice became completely tumour-free. Lactate also significantly improved the effects of a cancer-fighting vaccine and improved the anti-cancer response of cultured T cells that were injected into tumour-bearing mice.

Further single-cell RNA sequencing analysis showed that more T cells infiltrated the tumours 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.

“The lactate that we usually think of as a waste product appears to have a previously unrecognised role in fighting cancer,” Gao said.

Gao said the data suggest that lactate could be used to supplement existing immunotherapies, such as immune checkpoint inhibitors, cancer vaccines and CAR-T cell therapy — a cancer treatment in which T cells engineered to fight specific tumour types are expanded in the laboratory and then injected into patients. 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.

Image shows single-cell transcriptome analysis enrichment of tumour-infiltrating T cells — the red dots — after lactate treatment.

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