Researchers at the University of Pennsylvania have uncovered how tumor-nibbling T cells can have the unintended effects of helping cancer elude immune response.
The immune system helps the body combat bacteria, parasites, and bacteria that are coming into it. Also, it aids in dealing with internal hazards such as cancer.
However, the immune system can often be overwhelmed by malignancies. This makes it possible for tumors to escape being detected and destroyed.
This new study published in the journal Cell Metabolism revealed how T cells can trigger a process that can help cancer elude immune response. The process reduces the efficiency of cancer therapies, including the promising CAR T-cell therapy.
Results of this research can aid in improving the efficacy of cancer treatments.
Trogocytosis and immune response
This work uncovered how tumor-derived factors set off a process known as trogocytosis. “Trogo” is a Greek word that means “to chew” or “to gnaw.”
Researchers say T cells can “nibble” the cancer cell membrane in their interaction with tumor cells. If the nibbled membrane piece contains an antigen or a cancer-specific molecule, a T cell could start expressing the cancer antigen on its surface. This can make the immune cell become a target of other T cells, which see it as a cancer cell.
Lead researcher Serge Y. Fuchs noted that trogocytosis can lead to three things, all of which are awful for a cancer patient.
“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 cells come along, it will not recognize it, giving cancer cells a window of opportunity to grow unchecked,” explained Fuchs. “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.”
Trogocytosis not only affects the natural T cells of a patient but also those engineered into CAR-T cells. The latter are T cells removed from a patient’s blood, genetically engineered in a lab, and then transferred back to the patient.
The summary of what trogocytosis causes is a decline in protective T cells and their activity as well as more opportunities for cancer cells to evade detection and thrive.
Insights for improving anti-cancer therapies
Fuchs and his team have been studying tumor-derived factors and the roles they play in helping cancer evade T cells. These comprise lipids, proteins, and other materials that tumor cells release into the body.
The University of Pennsylvania researchers found in this study that tumor-derived factors impeded the ability of T cells to fight cancer. They observed a huge fall in the levels of CH25H, a gene involved in the alteration of a cell’s lipid membranes.
CH25H blocks separate cell membranes from fusing, thereby impeding a prerequisite for trogocytosis. The researchers were able to keep trogocytosis from occurring by introducing a metabolite made by the gene.
This finding disproves the earlier belief that trogocytosis results simply from the ability of tumors to block anti-cancer immunity.
Another interesting finding was that a different gene called ATF3 counters CH25H to aid trogocytosis. When the ATF3 gene was removed, the process was impeded and T cells got an extra boost to destroy tumor cells.
This research reveals new targets for cancer therapies and how CAR-T cell therapy can be made more effective. The team found that combining CAR-T cells with CH25H boosted survival in mouse models of cancer, compared to when only CAR-T cells were used.
Fuchs and his fellow researchers are planning to learn more about the roles ATF3, CH25H, and other molecules play in trogocytosis in future research. They are also hoping other scientists would join in similar research to bring their results closer to clinical use.