Researchers Uncover CAR Molecule Transfer Mechanism

Engineered immune cells known as CAR-T cells play a crucial role in cancer treatment. Researchers at Uppsala University have now discovered that CAR molecules can transfer from CAR-T cells to other T cells within the tumor microenvironment.

In addition to identifying this transfer, the team has uncovered the underlying regulatory mechanisms, which could lead to more effective CAR-T cell therapies. Their findings were recently published in Science Immunology.

Immune cells naturally exchange surface molecules in a process called trogocytosis, which can shape the immune response by allowing proteins to pass between cells. CAR-T cells—genetically modified immune cells designed to target specific cancers—carry CAR molecules on their surface, which are key to their therapeutic function. This study revealed that CAR molecules can be transferred from engineered cells to other T cells via trogocytosis.

While trogocytosis has been known for some time, its regulatory mechanisms have remained unclear. The prevailing theory suggested that an integral membrane protein could only be exchanged if it is bound to a corresponding receptor on another immune cell. However, this new research challenges that idea.

"Our study disproves this hypothesis. We show that while cell-to-cell contact is required, a specific molecule does not need a binding partner on another cell to undergo trogocytosis. Instead, the surrounding membrane region determines whether a molecule can be transferred," said Stefano Barbera, postdoctoral researcher and corresponding author.

"The fact that CAR molecules do not bind to receptors on other T cells further contradicts the old model of trogocytosis regulation. We're excited to contribute new biological insights into this process," added Anna Dimberg, one of the study’s senior authors.

The implications of CAR trogocytosis in cancer therapy remain uncertain. A key question is whether enhancing or limiting this transfer could improve treatment outcomes or reduce side effects.

"Now that we understand how to regulate trogocytosis, we can design CAR molecules with or without this capability, test them in advanced models, and eventually evaluate their impact in clinical trials," said Magnus Essand, the study’s second senior author.

This discovery opens new possibilities for refining CAR-T cell therapies, offering potential strategies to enhance their effectiveness and safety. Further research will determine how best to apply these findings in clinical settings.