Blocking a protein responsible for importing lactic acid, a byproduct of cancer cell metabolism, revitalized exhausted T cells and improved tumor management in mouse models, as revealed in a recent study. This research highlights how limiting T cell exposure to inhibitory metabolites might be a novel strategy for cancer immunotherapy.
As cancer grows, cells release various metabolic byproducts like lactic acid into their surrounding environment. This lactic acid is taken in by exhausted T cells—cells that have lost their effectiveness in fighting cancer—which further drains their energy, according to new findings from the University of Pittsburgh and UPMC Hillman Cancer Center.
Researchers discovered that when they halted the protein responsible for lactic acid importation, tired T cells experienced a revitalization, leading to enhanced tumor control in mouse models. The findings have been published in Nature Immunology.
“Preventing access to inhibitory metabolites offers a fresh perspective on how we can rejuvenate the immune system,” stated Greg Delgoffe, Ph.D., the senior author and professor of immunology at Pitt and director of the Tumor Microenvironment Center at UPMC Hillman. “While we often view exhausted T cells as ineffective, this study demonstrates that we can actually enhance their function by blocking the detrimental effects of the tumor environment.”
When T cells are exposed to tumors over time, they gradually become less effective due to the activation of coinhibitory receptors, which serve as brakes. Progenitor exhausted T cells still possess some cancer-fighting ability but can deteriorate further into a terminally exhausted state. Most current immunotherapies, including checkpoint inhibitors like anti-PD1 and anti-CTLA4, aim to disable these braking systems.
Delgoffe noted, “Checkpoint inhibitors are pivotal in our immunotherapy toolkit and have shown remarkable success for certain patients and cancers. However, there have been many disappointments, and they haven’t transformed outcomes across all cancer types as anticipated. There’s a limit to how much you can accomplish just by releasing the brakes.”
Delgoffe and first author Ronal Peralta, Ph.D., a postdoctoral researcher in Delgoffe’s lab, explored a group of proteins known as solute carriers that help transport nutrients into cells, searching for innovative ways to rejuvenate worn-out T cells.
Peralta remarked, “Exhausted T cells have been extensively studied for their lost abilities, but we wanted to discover what they are still capable of. What nutrients do they access? These were the questions guiding our research.”
He found that a solute carrier called MCT11, responsible for importing lactic acid, was significantly elevated in terminally exhausted T cells compared to their progenitor counterparts, indicating lactic acid’s role in their decreased functionality.
By knocking out the gene for MCT11 in mice or inhibiting the protein with a monoclonal antibody, T cells absorbed less lactic acid and exhibited enhanced functionality and tumor control in mouse models of melanoma, colorectal cancer, and head and neck cancer.
Using an analogy, if coinhibitory receptors represent the brakes on a vehicle, lactic acid serves as poor-quality fuel that hampers its performance. By blocking access to this substandard fuel source, the car can utilize better fuel, thereby improving its performance—a parallel to blocking MCT11 that prevents T cells from accessing the lactic acid that disrupts their function.
“Eliminating MCT11 doesn’t change the expression of coinhibitory receptors on T cells,” Delgoffe clarified. “They remain technically exhausted, yet they function like active T cells because we’ve stopped their intake of the detrimental metabolite, lactic acid.”
The MCT11 antibody alone proved effective in enhancing tumor clearance in mice, but its efficacy was even greater when combined with anti-PD1 treatments.
Through their spinout company, Delgoffe and Peralta are now focused on optimizing the MCT antibody for human T cells, with hopes of testing it in future clinical trials.
Peralta believes MCT11 is a promising therapeutic target because it is predominantly found in exhausted T cells, which are largely localized in tumors. This specificity means drugs targeting MCT11 could result in fewer side effects compared to traditional immunotherapies like anti-PD-1, which affect T cells throughout the body.
“This study is thrilling because it demonstrates that modifying T cell interactions with their surrounding metabolites can lead to better cancer treatment outcomes,” stated Peralta. “It encourages further exploration of other potential targets in immune cells for treating cancer and various other diseases.”
Other contributors to the study included Bingxian Xie, Ph.D., Konstantinos Lontos, M.D., Ph.D., Hector Nieves-Rosado, Ph.D., Kellie Spahr, Supriya Joshi, Ph.D., Rhodes B. Ford, Kevin Quann, M.D., Ph.D., Andrew Frisch, Victoria Dean, Mary Philbin, Anthony R. Cillo, Ph.D., Sebastian Gingras, Ph.D., Amanda C. Poholek, Ph.D., Lawrence P. Kane, Ph.D., and Dayana B. Rivadeneira, Ph.D., all affiliated with Pitt and UPMC.
This research received support from the National Institutes of Health (DP2AI136598, P50CA121973, P50CA097190), the National Institute of Allergy and Infectious Diseases (R01AI171483, R01AI166598), the Hillman Fellows for Innovative Cancer Research Program, Stand Up to Cancer (SU2C-AACR-IRG-04-16), the Alliance for Cancer Gene Therapy, the Mark Foundation for Cancer Research’s Emerging Leader Award, a Cancer Research Institute Lloyd J. Old STAR Award, and the Sy Holzer Endowed Immunotherapy Fund.
