Hyperactive Rac stimulates cannibalism of living target cells and enhances CAR-M-mediated cancer cell killing

The 21kD GTPase Rac is an evolutionarily ancient regulator of cell shape and behavior. Rac2 is predominantly expressed in hematopoietic cells where it is essential for survival and motility. The hyperactivating mutation Rac2^E62Kalso causes human immunodeficiency, although the mechanism remains unexplained. Here, we report that in Drosophila, hyperactivating Rac stimulates ovarian cells to cannibalize neighboring cells, destroying the tissue. We then show that hyperactive Rac2^E62Kstimulates human HL60-derived macrophage-like cells to engulf and kill living T cell leukemia cells. Primary mouse Rac2^+/E62Kbone-marrow-derived macrophages also cannibalize primary Rac2^+/E62KT cells due to a combination of macrophage hyperactivity and T cell hypersensitivity to engulfment. Additionally, Rac2^+/E62Kmacrophages non-autonomously stimulate wild-type macrophages to engulf T cells. Rac2^E62Kalso enhances engulfment of target cancer cells by chimeric antigen receptor-expressing macrophages (CAR-M) in a CAR-dependent manner. We propose that Rac-mediated cell cannibalism may contribute to Rac2^+/E62Khuman immunodeficiency and enhance CAR-M cancer immunotherapy.