A new approach reactivates exhausted T cells to improve tumor control

As cancer cells proliferate, they export metabolic byproducts, such as lactate, into the tumor microenvironment. Depleted T cells – people who have lost their ability to fight cancer – new research from the University of Pittsburgh and UPMC Hillman Cancer Center shows that ingesting this lactic acid further robs you of energy.

When researchers blocked a protein that allows lactate to enter cells, exhausted T cells gained new life, leading to improved tumor control in mouse cancer models. The survey results are announced today. Innate immunology.

Blocking access to inhibitory metabolites is a completely new way of thinking about how to reactivate the immune system. We often think of exhausted T cells as useless, but this study shows that we can actually get the juice out of these cells by blocking the negative effects of the tumor microenvironment. ”

Dr. Greg Delgoff senior writer, Professor of Immunology at Pitt University and Director of the UPMC Hillman Tumor Microenvironment Center

Continued exposure to tumors gradually reduces the effectiveness of T cells due to the expression of co-inhibitory receptors that act like brakes. T cells that are depleted of their progenitors still retain some cancer-killing ability and can deteriorate further and eventually become depleted. Most immunotherapies, including the checkpoint inhibitors anti-PD1 and anti-CTLA4, attempt to release these brakes by blocking co-inhibitory receptors.

“Checkpoint inhibitors are our main weapon. immunotherapy “Although Arsenal's research has had incredible successes for some patients with certain cancers, there have also been many failures, and in many cancers we have not had the major breakthroughs we had hoped for. It wasn’t transformative,” Delgoffe said. Take your foot off the brake. ”

In search of new ways to revitalize tired T cells, lead author Ronal Peralta, Ph.D., a postdoctoral fellow in Delgoffe and Delgoffe's lab, focused on a family of proteins called solute carriers that transport nutrients into cells. I started with

“Depleted T cells have been extensively studied in terms of what they can no longer do,” Peralta said. “But what? do Is this what happens to exhausted T cells? what do they eat? What nutrients can they get? These questions were the starting point for our research. ”

Dr. Peralta found that a solute carrier called MCT11, which transports lactate, is dramatically increased in terminally exhausted T cells compared to their progenitor cells, suggesting that lactate contributes to the loss of function. It suggests that.

When he deleted the gene encoding MCT11 in mice or blocked the protein with a monoclonal antibody, T cells took up less lactate and showed improved functionality and tumor control in mouse models. melanomacolorectal cancer and head and neck cancer.

If the co-inhibitory receptors that cause T-cell depletion are your car's brakes, then lactic acid is like a low-quality gas contaminated with dirt and particles that hinder your car's performance. By blocking access to gas stations that sell this substandard fuel, cars get better gas and their performance improves. Blocking MCT11 is equivalent to preventing T cells from accessing lactate, which inhibits their function.

“Deleting MCT11 makes no difference in the expression of co-inhibitory receptors on T cells,” Delgoffe explained. “They are still technically exhausted, but because we have cut off their supply of this bad metabolite, lactate, they function as functional T cells.”

The researchers found that while the MCT11 antibody promoted tumor clearance in mice when administered alone, it was even more effective when combined with an anti-PD1 antibody.

Delgoffe and Peralta, through a new spin-out company, are currently working to optimize the MCT antibody for efficacy in human T cells, with the goal of testing it in future clinical trials.

MCT11 is an attractive therapeutic target because it is expressed almost exclusively on depleted T cells concentrated in tumors, Peralta said. This means that drugs that target MCT11 may have fewer side effects than traditional immunotherapies such as anti-PD-1, which act on T cells throughout the body.

“This study is very exciting because it is a proof of concept that targeting how T cells interact with metabolites in the environment can promote better outcomes in cancer. ” Peralta said. “This opens the door to exploring how we can track other targets within immune cells to treat cancer and many other diseases.”

Other authors of this study are Bingxian Xie, PhD, Konstantinos Lontos, MD, Hector Nieves-Rosado, PhD, Kellie Spahr, Supriya Joshi, PhD, Rhodes B. Ford, Kevin Kuang, MD, Andrew Frisch, Victoria Dean, Mary • Philbin, Anthony R. Schiro, Ph.D., Dr. Sebastian Gingras, Dr. Amanda C. Pohorek, Dr. Lawrence P. Cain, and Dr. Dayana B. Rivadeneira, all of Pitt and UPMC;

This research was supported by the National Institutes of Health (DP2AI136598, P50CA121973 and P50CA097190), the National Institute of Allergy and Infectious Diseases (R01AI171483, R01AI166598), and the Hillman Fellows Innovative Cancer Research Program, Stand Up to Cancer (SU2C-AACR-). I received it. IRG-04-16), against allied cancers gene therapythe Mark Foundation for Cancer Research's Emerging Leader Award, the Cancer Research Institute Lloyd J. Old STAR Award, and the Sy Holzer Endowed Immunotherapy Fund.