Disruption of SIRPα signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts

摘要: Although tumor surveillance by T and B lymphocytes is well studied, the role of innate immune cells, in particular macrophages, less clear. Moreover, existence subclonal genetic functional diversity some human cancers such as leukemia underscores importance defining mechanisms that effectively target disease-sustaining cancer stem cells addition to bulk cells. In this study, we report cell function xenotransplant models acute myeloid (AML) depends on SIRPα-mediated inhibition macrophages through engagement with its ligand CD47. We generated mice expressing SIRPα variants differential ability bind CD47 demonstrated macrophage-mediated phagocytosis clearance AML depend absent signaling. obtained independent confirmation restriction observed our mouse using SIRPα-Fc fusion protein disrupt SIRPα–CD47 engagement. Treatment enhanced both impaired leukemic engraftment mice. Importantly, treatment did not significantly enhance normal hematopoietic targets. These findings support development therapeutics antagonize signaling elimination AML.