Hijacking TYRO3 from Tumor Cells via Trogocytosis Enhances NK-cell Effector Functions and Proliferation

Trogocytosis is a fast, cell-cell contact-dependent uptake of membrane patches and associated molecules by one cell from another. Here, we report our investigation of trogocytosis of TYRO3, a cell membrane protein, from tumor target cells to natural killer (NK) cells and the associated functional consequences for NK cells. We found that although NK cells did not express endogenous TYRO3 on the cell surface, activated NK cells rapidly acquired TYRO3 from tumor cells via trogocytosis in vitro and in vivo. NK cells that acquired TYRO3, which we termed TYRO3⁺ NK cells, had significantly enhanced cytotoxicity and IFNγ production as well as higher expression of some activated surface markers compared with TYRO3^- NK cells. Furthermore, the activation status of NK cells and TYRO3 expression levels on donor cells, either endogenous or ectopic, positively correlated with trogocytosis levels. When the antigen-presenting cell (APC) K562 leukemia cell line, a feeder cell line to expand NK cells, overexpressed TYRO3, TYRO3 was transferred to NK cells via trogocytosis, which improved NK-cell proliferation ex vivo. This provides a strategy to manufacture NK cells or their engineered counterparts, such as chimeric antigen receptor NK cells, for the treatment of cancer or infectious diseases.