Lactate Found to Rejuvenate Cancer-Targeting Immune Cells

Lactate is a key metabolite produced from glycolytic metabolism of glucose and serves as a fuel source for various cell types. Lactate’s effects have been hard to predict within tumor microenvironments, making this cellular byproduct an untraditional target for cancer research. To address these discrepancies in the literature, a team of researchers from UT Southwestern’s Simmons Cancer Center investigated lactate’s role in augmenting anti-tumor effects.

“The lactate that we usually think of as a waste product appears to have a previously unrecognized role in fighting cancer,” said Jinming Gao, Ph.D., co-author of the study and Professor of Cell Biology, Otolaryngology – Head and Neck Surgery, and Pharmacology, and member of the Harold C. Simmons Comprehensive Cancer Center. 

The team’s paper, published in the journal Nature Communications, found that lactate rejuvenated immune cells that fight against cancer, showing the potential to augment anti-tumor effects of existing immunotherapies. Contrary to lactic acid’s immunosuppressive effects, the team uncovered an immune protection role of sodium lactate by boosting stem-like CD8+ T cells in cancer treatment.

To probe lactate’s role in the tumor microenvironment, the researchers gave lactate injections to both male and female mice with colon cancer or melanoma. They also gave glucose injections to other tumor-positive mice as a control.

The authors found that, while glucose had little effect on the mice with cancer, tumor growth was significantly reduced in the mice injected with lactate. To further probe these findings, the team then repeated the experiment in genetically modified mice lacking T cells. They found that this previously observed anti-tumor effect was blocked, suggesting that lactate may exert its effects by influencing immune cells.

While administering lactate alone didn’t entirely eliminate any tumors, adding an immune checkpoint inhibitor resulted in about half of the mice population being tumor-free. Lactate was also found to improve the effectiveness of a cancer-fighting vaccine and the anti-cancer response of cultured T cells injected into tumor-bearing mice.

Dr. Gao suggested that the team’s data could be used to supplement already established immunotherapies, such as cancer vaccines, immune checkpoint inhibitors, and CAR-T cell therapies. It also suggests that exercise, an activity that naturally raises lactate levels, may be protective against cancer or positively augment the immune system to better defend itself against cancer. Dr. Gao and colleagues plan to investigate these cellular mechanisms in future work.