Cancer cells produce metabolic byproducts such as lactic acid as they grow, which they pump into the tumor microenvironment. This lactic acid saps the energy of exhausted T cells, which have lost their effectiveness in fighting cancer. Researchers from the University of Pittsburgh and UPMC Hillman Cancer Center discovered that blocking the protein responsible for importing lactic acid into cells can rejuvenate exhausted T cells. This led to improved tumor control in mouse models of cancer. The findings were published in Nature Immunology.
Exhausted T cells, which become less effective when continually exposed to tumors, express coinhibitory receptors that act as brakes on their function. These cells can deteriorate further to a terminally exhausted state. While many immunotherapies attempt to release these brakes with checkpoint inhibitors like anti-PD1 and anti-CTLA4, researchers sought a novel approach to reinvigorating exhausted T cells. By blocking negative effects of the tumor microenvironment, they found that exhausted T cells could regain their functionality and contribute to tumor control.
The researchers identified a solute carrier protein called MCT11, which is responsible for importing lactic acid, as being greatly increased in terminally exhausted T cells. Deleting the gene encoding MCT11 or blocking the protein in mice improved T cell functionality and tumor control in models of melanoma, colorectal carcinoma, and head and neck cancer. By preventing T cells from accessing lactic acid, their function was restored, even though they technically remained exhausted. This approach showed promise in promoting the clearance of tumors when used alone or in combination with anti-PD1.
The MCT11 antibody developed by the researchers demonstrated effectiveness in mouse models and is now being optimized for human T cells with the goal of testing it in future clinical trials. MCT11 is an attractive therapeutic target because it is predominantly expressed in exhausted T cells found in tumors, which could potentially reduce side effects compared to traditional immunotherapies. The researchers are optimistic about the potential of targeting how T cells interact with metabolites in their environment to improve cancer treatment outcomes and potentially address other diseases.
The study’s authors are working to explore other targets in immune cells for treating cancer and other diseases, building on the success of their research. The research was supported by grants from organizations such as the National Institutes of Health, the National Institute of Allergy and Infectious Disease, the Hillman Fellows for Innovative Cancer Research Program, Stand Up to Cancer, the Alliance for Cancer Gene Therapy, and the Mark Foundation for Cancer Research, among others. This research represents a significant advance in understanding how metabolites in the tumor microenvironment impact T cell exhaustion and the potential for new therapeutic approaches in cancer treatment.