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Trogocytosis helps tumours evade the immune response

Written by Lauren Robertson, Science Writer

In a new study, published in Cell Metabolism, researchers at the University of Pennsylvania have discovered the mechanism by which tumours evade the immune system. A better understanding of this process could not only provide new targets for immunotherapies, but help improve the efficacy of current treatments such as CAR T cells.

What is trogocytosis?

Trogocytosis occurs when a B, T, or NK cell “nibbles” an antigen-presenting cell and extracts molecules from the cell membrane to then express on their own surface. In the case of cancer, a T cell may then start expressing the tumour antigen on their surface, fooling the immune system into thinking it is cancer. This can affect both the patient’s own T cells, as well as those modified to become CAR T cells in therapy.

The issue with trogocytosis is three-fold, as explained by lead author Serge Y. Fuchs: “First of all, the tumour 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 tumour cell membrane, it becomes much less active. And the third problem is very ironic. Because now, a T cell that displays tumour antigen – this “sheep in wolf’s clothing” – may then fall victim to “fratricide,” and be killed by another T cell.”

One potential reason this process may have been overlooked in the past is because it is much like “studying a vanishing act,” notes Fuchs. Only a few T cells are subjected to this process, and once they are, they disappear very quickly. Despite the challenges, Fuchs’ team decided to study trogocytosis in more detail.  

Figure 1 – The underlying mechanism of trogocytosis. Here you can see an outline of the genes and associated metabolites involved in the trogocytosis process. CTL (cytotoxic T lymphocyte), TDF (tumour-derived factors).

The mark of a killer (T cell)

The team began by collecting the tumour-derived factors (TDFs) from a cancer and exposing T cells to them in solution. What they observed was that these T cells showed a marked reduction in their ability to fight cancer.

On closer inspection, the team noticed a significant decline in the levels of the CH25H gene, which is known to be involved in altering the lipid membrane of a cell. Specifically, this gene inhibits two cell membranes from fusing together – a process that is essential in trogocytosis.

When the metabolite associated with this gene (25-hydroxycholesterol) was added back into the solution, the T cells were once again able to block trogocytosis. Further characterisation identified a second player, the ATF3 gene, that has the opposite effect to CH25H. Again, knocking out this gene saw T cell activity restored, providing evidence that both of these genes could form important targets for future research.

Improving CAR T cell therapy

There are obvious applications for these findings in identifying novel targets for immunotherapies.  In the more immediate term, they could also drastically improve the effectiveness of current CAR T cell therapies through blocking trogocytosis. “We figured, why don’t we use what is cleverly known as an ‘armored CAR’ approach, and co-express CH25H in the CAR T,” Fuchs added. “This turned out to be more efficient than the old CAR T cells.”

Only a small number of T cells are involved in trogocytosis, but the authors suggest the impact of this process on a cancer’s ability to evade the immune system could be vastly underappreciated. In the future, Fuchs and his team want to explore the roles of ATF3 and CH25H, as well as other molecules, in trogocytosis and hope to see more clinical application of their exciting findings.