Engineered immune cells called CAR-T cells are used in the treatment of cancer. Researchers from Uppsala University have now discovered that CAR molecules can be transferred from the CAR-T cells to other T cells in the tumour microenvironment. The researchers also pinpoint how this transfer is regulated, which may be used to improve the efficacy of CAR-T cell therapy. The study has been published in the journal Science Immunology.

Immune cells have a capacity to exchange cell surface molecules between one another. This exchange is called trogocytosis and may potentially impact the immune response since it allows different proteins to be transferred between cells.

Chimeric antigen receptor (CAR)-T cells are genetically engineered immune cells that are used in therapies against several cancer types. The CAR molecules, which mediate the therapeutic effect of CAR T cells, are located on the cells surface. In the current study, the researchers discovered that CAR molecules can be transferred from the engineered cells to other T cells through trogocytosis.

The process behind trogocytosis has been known for some time but how it is regulated has remained unclear. The proposed hypothesis has been that an integral membrane protein is exchanged by trogocytosis if it binds to a corresponding receptor on the surface of another immune cell.

“Our study disproves this hypothesis and we demonstrate that although cell–cell contact is needed, a specific molecule does not need a corresponding receptor on another cell to be trogocytosed. Instead, it is the membrane region surrounding the cell surface molecule that determines whether it can be transferred or not,” says Stefano Barbera, postdoctoral researcher at the Department of Immunology, Genetics and Pathology, who is first and corresponding author of the study.

“The fact that CAR molecules do not have a binding partner on other T cells further disproves the old hypothesis on how trogocytosis is regulated. We are very excited to be able to contribute with new biological insights to this process,” says Anna Dimberg, one of the senior authors of the study.

The biological role of CAR trogocytosis during CAR-T cell therapy of cancer is still unknown. An open question is whether increased or reduced trogocytosis can lead to better efficacy and/or reduced side effects.

“Now when we know how to regulate trogocytosis we can design CAR molecules with and without the capacity to trogocytose and evaluate the different CAR molecules in advanced model systems and hopefully at a later stage in a clinical trial,” says Magnus Essand, the second senior author of the study.

Publication:
Barbera S, Schuiling MJA, Sanjaya NA, Pietilä I, Sarén T, Essand M*, Dimberg A*. Trogocytosis of Chimeric Antigen Receptors between T cells is regulated by their transmembrane domains. Science Immunology, doi: 10.1126/sciimmunol.ado2054, 2025. *ME and AD are shared senior authors.