New research from the University of Pittsburgh and UPMC Hillman Cancer Center suggests that targeting the way immune cells absorb lactic acid could help reinvigorate exhausted T cells, enhancing their ability to fight cancer. The study, published in Nature Immunology, shows that blocking the protein responsible for transporting lactic acid into T cells not only improves the function of T cells cells but also improved tumor control in mouse models of cancer.
Exhausted T cells are a significant challenge in cancer immunotherapy. Previous research has shown that the tumor microenvironment (TME), filled with high levels of metabolic byproducts like lactic acid, contributes to T cell exhaustion. However, the exact role of lactic acid in this process has remained unclear.
The new study has uncovered that lactic acid, a metabolic waste product of tumor cells, is consumed by T cells, which saps their energy and ability to fight tumors. By blocking the protein that is responsible for importing lactic acid into T cells, the researchers were able to rejuvenate exhausted immune cells.
“Blocking access to inhibitory metabolites is a completely new take on how we can reinvigorate the immune system,” said senior author Greg Delgoffe, PhD, professor of immunology at Pitt and director of the Tumor Microenvironment Center at UPMC Hillman. “We often think of exhausted T cells as being useless, but this study shows that we can actually get juice out of these cells by blocking the negative effects of the tumor microenvironment.”
The team’s experiments focused on a class of proteins known as solute carriers, which are responsible for transporting various metabolites, including lactic acid, into cells. First author Ronal Peralta, PhD, a postdoctoral fellow in Delgoffe’s lab, found that MCT11, a solute carrier that imports lactic acid, was significantly upregulated in exhausted T cells compared to less exhausted, progenitor T cells. This led the researchers to hypothesize that lactic acid could be contributing to T cell dysfunction.
When the team deleted the gene encoding MCT11 or blocked the protein with a monoclonal antibody, the T cells ingested less lactic acid and showed improved tumor control in mouse models of melanoma, colorectal carcinoma, and head and neck cancer.
“When we get rid of MCT11, there’s no difference in the expression of coinhibitory receptors on T cells,” Delgoffe said. “They’re still technically exhausted, but they behave as functional T cells because we cut off the tap of this bad metabolite, lactic acid.”
In their animal models, the MCT11 monoclonal antibody not only promoted tumor clearance on its own but was even more effective when combined with an immune checkpoint inhibitor, anti-PD1. This combination therapy could be a promising new approach for improving the efficacy of existing immunotherapies.
The researchers believe that MCT11 is an attractive therapeutic target because it is almost exclusively expressed in exhausted T cells, which are concentrated within tumors. This makes it a potentially more selective and targeted treatment option compared to other immunotherapies, such as anti-PD1, which affect T cells throughout the body and may cause more widespread side effects.
“This research is really exciting because it’s proof-of-concept that targeting how T cells interact with metabolites in their environment can promote better outcomes in cancer,” said Peralta. “It opens the door for exploring how we can go after other targets in immune cells for treating cancer and many other diseases.”
The research team is now working to optimize the MCT11 antibody for use in human clinical trials. They hope that targeting MCT11 could provide a more effective and less toxic alternative to current immunotherapies.
