Paper published today in Nature shows how chemicals in the areas around tumors – known as the tumor ‘s microenvironment – overwhelm the immune system and allow cancer to escape invasion. These findings suggest that an existing drug may enhance cancer immunotherapy.
The study was conducted by a team of scientists at the UPMC Hillman Cancer Center and the University of Pittsburgh School of Medicine, led by Greg Delgoffe, Ph.D., associate professor of Pitt immunology. By disrupting the microenvironmental impact of the tumor on immune cells in mice, the researchers were able to reduce tumors, extend survival and increase sensitivity to immunotherapy.
Most people do not respond to immunotherapy. The reason is that we don’t really understand how the immune system is regulated within the microenvironment of this modified tumor. “
Greg Delgoffe, Ph.D., Pitt Associate Professor of Psychology
The immune system is made up of many types of cells, most notably T cells. One type, called killer T cells, fights invaders, such as viruses, bacteria and even cancer. Another type, called regulatory T cells, or “T-reg cells” for short, is resistant to killing T cells by acting as protectors of the cells belonging to the body. T-reg cells are important for preventing autoimmune diseases, such as type I diabetes, Crohn’s disease and multiple sclerosis, where lethal killer T cells attack the body’s healthy bones.
For these different immune cells to do their job, they need to produce energy. The Delgoffe team studied how different types of T cells have different flavors, and how tumors – which have large flavors – compete for nutrition with infiltrating immune cells. The researchers found that killer T cells and regulatory T cells have different flavors, and cancer cells take advantage of this.
“Cancer is wise for the whole situation,” Delgoffe said. “Cancer cells not just destroy the T cells that would kill them but feed those regulatory T cells that would protect them.”
Delgoffe’s team soon discovered that tumors pick up the vital nutrients nearby that need to attack to kill T cells. Further, they also release lactic acid, which feeds the regulatory T cells, causing them to guard. T-regs can convert lactic acid into energy, using a protein called MCT1, so going up with the eardrum is a great way for these immune cells to be fed.
“What better way to recruit a cell than food?” Delgoffe said.
Then, using mice with melanoma, the researchers found that mutating the gene that codes for MCT1 proteins caused tumor growth to slow down. The mice also lived longer.
“We made the T-regs hungry,” Delgoffe said. “When T-reg cells are not maintained by the eardrum, killing T cells can come in and kill the cancer.”
Importantly, when the Delgoffe team combined MCT1 inhibition with immunotherapy, the anti-cancer effects were stronger than either strategy alone.
Clinically, the same effect could be achieved with the use of drugs that inhibit MCT1 – one of which is currently being diagnosed in people with advanced lymphoma, and it seems to be he suffers well.