Tumor-associated CD47 regulation of the phagocyte oxidase shapes innate and adaptive immune responses during anti-tumor antibody therapy 4273

Description Antibody-dependent cellular phagocytosis (ADCP) is an important, yet understudied effector mechanism contributing to the depletion of cancer cells. CD47 on tumors suppresses ADCP by engagement of SIRPa on macrophages and neutrophils. Here, we have found a new role for tumor-associated CD47 in regulating the phagocyte oxidase (NOX2), which in turn regulates adaptive T and B cell responses. CRISPR deletion of CD47 renders syngeneic B16F10 subcutaneous melanoma tumors susceptible to anti-Tyrp1 IgG-mediated destruction with ∼33% of mice attaining cure, of which ∼50% have durable immunity to a second tumor challenge. In contrast, anti-Tyrp1 provides no benefit when mice are inoculated with wild-type B16F10. Enhancing T cell activation via anti-PD1 blockade or IL-2 fused to mouse serum albumin modestly improves tumor clearance, with cure in attained in ∼60% of mice. In contrast, syngeneic CD47-/- B16F10 tumors in NOX2 deficient mice, treated with anti-Tyrp1 all meet endpoint, suggesting a requirement for NOX2 activity in for T cell cytolytic activity or T cell help. Surprisingly, combining anti-Tyrp1 with either PD-1 blockade or IL-2 leads to robust tumor clearance in 80-90% of NOX2 deficient mice, arguing that NOX2 can also limit T cell activation when checkpoint blockade or IL-2 support activation. Taken together, this work indicates that CD47 regulation of NOX2 shapes macrophage ADCP responses through interactions with the adaptive immune system. Funding Sources Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number U01AI148153. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)