T cells that ‘nibble’ tumors unwittingly help cancer evade the immune response

The immune system is equipped to respond not just to external invaders — think viruses, bacteria, and parasites — but also to internal threats, namely, cancer. Yet, frequently, malignancies overcome the immune system’s defenses and evade detection.

In a new study, researchers led by Serge Y. Fuchs of the School of Veterinary Medicine, have uncovered a detailed mechanism by which tumors can skirt both the immune system and cancer therapies that leverage its power, such as genetically engineered CAR T cells.

Their investigation, published in the journal Cell Metabolism, revealed how tumor-derived factors stimulate trogocytosis — a process derived from the Greek word trogo, which means “to gnaw” or “to chew.” When T cells interact with cancer cells, they can sometimes “nibble” a piece of the cancer cell membrane. When that membrane segment includes an antigen, a molecule specific to the cancer, the T cells may then begin expressing that antigen on their own cell surface, making it appear to other T cells like a cancer cell.

Trogocytosis can affect a patient’s own T cells and those modified to become CAR T cells, an approach in which a patient’s T cells are genetically engineered to specifically target cancer cells, grown in a lab, 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,” says Fuchs, the senior author on the work. “First of all, the tumor cell did not get killed and has lost an antigen, which may mean that even if another, better equipped T cell comes along, it will not recognize it, giving cancer cells a window of opportunity to grow unchecked. The second problem is, for reasons we still don’t understand, once a T cell takes a piece of the tumor cell membrane, it becomes much less active. And the third problem is very ironic. Because now, a T cell that displays tumor antigen, this ‘sheep in wolf’s clothing,’ may then become victim to ‘fratricide,’ killed by another T cell.” Overall, the result is a decline in killer T cell numbers and activity and a bump in opportunities for the cancer cells to escape detection and grow.

“What we see is that only a small number of cells undergo trogocytosis and then they disappear quickly because they’re killed. So we’re studying a vanishing act. It is hard to do — very expensive and very tedious — but it appears to be very important,” says Fuchs.

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