As cancer cells grow, they pump out metabolic byproducts such as lactic acid into the tumor microenvironment. Newly reported research by scientists at the University of Pittsburgh and UPMC Hillman Cancer Center suggests that exhausted T cells—which have lost their cancer-fighting vigor—consume this lactic acid, which further saps their energy. When the researchers blocked the solute carrier (SLC) protein MCT11, which imports lactic acid into cells, the exhausted T cells gained a new lease on life. Antibody blockade of MCT11 led to improved tumor control in mouse models of cancer when used as monotherapy, and also when combined with anti-PD1 immunotherapy.
“Blocking access to inhibitory metabolites is a completely new take on how we can reinvigorate the immune system,” said 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 being useless, but this study shows that we can actually get juice out of these cells by blocking negative effects of the tumor microenvironment.”
Delgoffe is senior author of the team’s published paper in Nature Immunology, titled “Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism,” in which they concluded “… this study suggests SLCs can be targeted on immune cells for therapeutic benefit.”
CD8+ T cells have a “crucial role” in orchestrating immune responses against pathogens and tumors, the authors wrote. However, when continually exposed to tumors, T cells progressively become less effective due to expression of coinhibitory receptors that act like brakes. Progenitor exhausted T cells, which still retain some cancer-killing function, can deteriorate further to a terminally exhausted state. “CD8+ T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME),” the team continued. “Exhausted T (Tex) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality.”
Most immunotherapies, including the checkpoint inhibitor drugs anti-PD1 and anti-CTLA4, attempt to release these brakes by blocking coinhibitory receptors. “Checkpoint inhibitors, which are the main weapons in our immunotherapy arsenal, have been incredibly successful for some patients with certain cancers, but there have also been a lot of failures, and they haven’t been the gamechangers we expected in many cancers,” said Delgoffe. “There’s only so much you can do by taking your foot off the brake.”
On the hunt for new ways to jumpstart tired T cells, Delgoffe and first author Ronal Peralta, PhD, postdoctoral fellow in Delgoffe’s lab, started by looking at the solute carrier family of proteins, which transport nutrients into cells.
“Exhausted T cells have been studied extensively in terms of what they can no longer do,” said Peralta. “But what do exhausted T cells do? What do they eat? What nutrients do they have access to? These questions were the starting point of our study.”
The researchers found that a solute carrier called MCT11, which imports lactic acid, was dramatically increased in terminally exhausted T cells compared to their progenitor versions, suggesting that lactic acid contributes to loss of function.
When the investigators then deleted the gene encoding MCT11 in mice or blocked the protein with a monoclonal antibody, T cells ingested less lactic acid and showed improved functionality and tumor control in mouse models of melanoma, colorectal carcinoma and head and neck cancer.” Conditional deletion of MCT11 in T cells reduced lactic acid uptake by Tex cells and improved their effector function,” the researchers reported. “Targeting MCT11 with an antibody reduced lactate uptake specifically in Tex cells, which, when used therapeutically in tumor-bearing mice, resulted in reduced tumor growth.”
The researchers found that the MCT11 antibody promoted clearance of tumors in mice when given alone, but in some mouse models was even more effective when combined with the checkpoint inhibitor anti-PD1. “MCT11 antibody blockade has an effect as a monotherapy, leading to complete responses in MC38 and MEER models and also as a combination therapy, doubling the CRs in mice bearing MC38 tumors in combination with αPD1,” they wrote.
If coinhibitory receptors that lead to T cell exhaustion are the brakes on a car, lactic acid is like poor quality gas contaminated with dirt and particulates that hinders the vehicle’s performance. By blocking access to the gas station that sells this subpar fuel, the car accesses better gas that improves its performance—just like blocking MCT11 stops T cells from accessing lactic acid that impedes their function. “When we get rid of MCT11, there’s no difference in the expression of coinhibitory receptors on T cells,” explained Delgoffe. “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 paper the authors concluded, “By modulating nutrient transporters, such as in the case of MCT11, terminally differentiated T cells can be rendered insensitive to metabolites such as lactic acid, driving tumor eradication and therapeutic response.” Through their new spinout company, Delgoffe and Peralta are now working to optimize the MCT antibody for effectiveness in human T cells, with the goal of testing it in future clinical trials.
According to Peralta, MCT11 is an attractive therapeutic target because it is almost exclusively expressed in exhausted T cells, which are concentrated in tumors. This means that drugs targeting MCT11 could have fewer side effects than traditional immunotherapies such as anti-PD-1, which act on T cells throughout the body. Reporting on their collective findings, the team suggested, “Short-term targeting of MCT11 in patients with cancer could, thus, limit the possibilities of potential toxicities and adverse autoimmune reactions.”
Peralta added, “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. It opens the door for exploring how we can go after other targets in immune cells for treating cancer and many other diseases.”
