CD47 suppresses phagocytosis by repositioning SIRPA and preventing integrin activation

Summary Macrophages must engulf dead cells, debris, and pathogens, while selecting against healthy cells to prevent autoimmunity. Healthy cells express CD47 on their surface, which activates the SIRPA receptor on macrophages to suppress engulfment. Cancer cells overexpress CD47 to evade clearance by the innate immune system, making the CD47-SIRPA signaling axis an appealing therapeutic target. However, the mechanism by which CD47-SIRPA inhibits engulfment remains poorly understood. Here, we dissect SIRPA signaling using a reconstituted target with varying concentrations of activating and inhibitor ligands. We find that SIRPA is excluded from the phagocytic synapse between the macrophage and its target unless CD47 is present. Artificially directing SIRPA to the kinase-rich synapse in the absence of CD47 activates SIRPA and suppresses engulfment, indicating that the localization of the receptor is critical for inhibitory signaling. CD47-SIRPA inhibits integrin activation in the macrophage, reducing macrophage-target contact and suppressing phagocytosis. Chemical activation of integrins can override this effect and drive engulfment of CD47-positive targets, including cancer cells. These results suggest new strategies for overcoming CD47-SIRPA inhibition of phagocytosis with potential applications in cancer immunotherapy.