Anticancer immune responses are hindered by cis interaction of inhibitory checkpoint SIRPα

Signal regulatory protein α (SIRPα) is a macrophage inhibitory receptor that limits phagocytosis and antitumor activity by interacting in trans with CD47 on tumor cells. Here, we found that a component of SIRPα’s inhibitory function occurred independently of CD47. Inhibition occurred because of interactions between SIRPα and CD18 (β 2 integrin) in cis on the surface of macrophages, involving SIRPα amino acids distinct from those implicated in the SIRPα-CD47 interaction. This cis interaction prevented activation of CD18, which is necessary for phagocytosis. The combined blockade of SIRPα-CD18 and SIRPα-CD47 was essential for maximizing phagocytosis and suppression of tumor growth in vivo. Thus, inhibitory immune checkpoints such as SIRPα suppress cell activation through a mechanism targeting CD18 in cis, which occurs in addition to engagement by their inhibitory checkpoint ligands in trans. This dual mode of action should be considered when developing inhibitory checkpoint blockades for immunotherapy.