The immune system is able to respond not only to external invaders – viruses, bacteria and parasites – but also to internal threats, namely cancer. However, often malignant tumors overcome the defenses of the immune system and elude detection.
In a new study, scientists led by Serge J. Fuchs at the School of Veterinary Medicine have uncovered a detailed mechanism by which tumors can bypass both the immune system and cancer treatments that use it, such as genetically engineered CAR T cells.
Their study, published in the journal Cell Metabolism, showed how tumor factors stimulate trogocytosis, a process derived from the Greek word trogo, which means to gnaw or chew. When T cells interact with cancer cells, they can sometimes “bite off” a piece of the cancer cell’s membrane. If this region of the membrane contains an antigen, a cancer-specific molecule, T cells can begin to express this antigen on their own cell surface, causing other T cells to perceive them as cancer cells.
Trogocytosis can affect the patient’s own T cells and T cells modified into CAR T cells, an approach in which a patient’s T cells are genetically engineered to specifically fight cancer cells, grown in a laboratory, and then delivered back to the patient.
“Trogocytosis can lead to three different things, and all three are bad for a person with a tumor,” said Fuchs, senior author of the paper. “Firstly, the tumor cell has not been killed and has lost the antigen, which could mean that even if another, better equipped T cell comes along, it will not recognize it, allowing the cancer cells to grow out of control. The second problem is that For some unknown reason, once the T cell takes over part of the membrane of the tumor cell, it becomes much less active. And the third problem is very paradoxical. Because now the T cell that displays the tumor antigen, this “sheep in wolf’s clothing,” can become a victim “fratricide” killed by another T-cell.” Overall, the result is a decrease in the number and activity of killer T cells and an increase in the ability for cancer cells to evade detection and grow.
Fuchs and his colleagues, who have long been interested in how receptors on the surface of immune cells control anti-cancer immunity, have made a number of discoveries that show how tumors can manipulate T-cells to avoid their defeat and destruction.
Of particular interest are the so-called tumor factors, or the mixture of proteins, lipids and other materials that cancer cells secrete into the body. In the current study, Pennsylvania scientists found that collecting these secretions and exposing T cells to the resulting solution interferes with the cells’ ability to do their job of fighting cancer.
“Just by exposing them to this tumor-conditioned environment, they killed fewer cancer cells, trogocytosed more, and died more,” Fuchs says.
It was previously thought that trogocytosis had something to do with cancer’s ability to interfere with cancer immunity, but Penn’s team identified the mechanism by showing that T cells exposed to tumor factors experienced a marked decrease in the CH25H gene. This gene is known to be involved in altering the lipid membranes of cells and may prevent the fusion of two cell membranes, which is necessary for trogocytosis. When they added back the metabolite produced by CH25H, they were able to block trogocytosis.
Further characterization of the pathway helped the team identify the ATF3 gene, which antagonizes CH25H activity. Elimination of AFT3 prevented trogocytosis and restored the ability of T cells to kill tumor cells. The new data not only suggest new targets for anti-cancer therapy, but may also have direct implications for CAR T therapy. Because trogocytosis can reduce the efficiency of engineered T cells delivered to CAR T, the researchers hypothesized that blocking it might increase the efficiency of CAR T.