T cells nibble at CAR T cells to gain antitumor immunity

While developing a way to get chimeric antigen receptor (CAR) T cells into the brain tumor microenvironment of mice, Stefano Barbera “bumped into” an entirely different discovery, he said. As a molecular biologist and new postdoctoral fellow in Anna Dimberg’s lab at Uppsala University, Barbera had planned to engineer multiple types of CAR T cells that would bind in different ways to brain endothelial cells. He had been preparing a mixture of T cells from different mouse strains, but while checking the quality of the mixture, he noticed that the T cells were exchanging molecules amongst themselves. This was completely unexpected, and when he first presented the data to his fellow lab members, he told them that he didn’t believe it.

“Eventually, everybody realized that this was real, that this was a biological thing,” said Barbera.

In a recent study in Science Immunology, he and his colleagues reported that T cells were swapping molecules via a process called trogocytosis, whereby cells come into close contact and nibble at each other’s plasma membranes to extract cellular material (1). Using flow cytometry to distinguish between cell populations, Barbera and his colleagues found that CAR T cells could engage in trogocytosis with T cells to deliver CARs across the plasma membrane — potentially arming T cells with their antitumor immunity.

Barbera and his colleagues also found that the probability that a particular protein will be transferred via trogocytosis depends on the structure of its transmembrane domain, which is a region made out of hydrophobic amino acids. “We believe that at the trogocytosis interface, there is a lot of cholesterol. When you have such thick membrane compartments, not all the proteins can enter,” said Barbera.

While the researchers don’t yet understand how this phenomenon will impact antitumor immunity, Barbera said, “I'm setting up studies now to understand if this is actually beneficial, because [from] a theoretical point of view, this could also be detrimental.”

Eventually, everybody realized that this was real, that this was a biological thing.
– Stefano Barbera, Uppsala University

Barbera explained that the benefits would be substantial if obtaining the CAR molecules allows regular T cells to suddenly see tumor cells and attack them. However, he noted that his team hasn’t found the recipient T cells to be efficient killers of cancer cells, like the CAR T cells are. That inefficiency could ultimately be counterproductive in fighting a tumor because the T cells could begin to express inhibitory molecules like PD-1 on their surface, leading to a signaling cascade that blocks the immune response.

Plus, there’s a third scenario that Barbera and his colleagues have to consider: Tumor cells can also steal CAR molecules from T cells via trogocytosis, essentially disarming the T cells’ ability to attack the cancer cells (2).

Moving forward, Barbera plans to study the aftereffects of T cells obtaining CAR molecules. He also wants to know whether designing the CAR protein with a different transmembrane domain could prevent tumor cells from engaging in trogocytosis with them.

Given how Barbera and his colleagues stumbled into the current results, he recognizes that he can’t predict what else these T cells have in store for them. “Everything was a surprise,” he said.

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