Binding of inhibitory checkpoints to CD18 in cis hinders anti-cancer immune responses

SIRPα is an inhibitory receptor on macrophages that limits phagocytosis and anti-tumor activity of macrophages by “ trans ” interacting with CD47 on tumor cells. Herein, we found that a large component of SIRPα’s inhibitory function occurred independently of CD47-binding and phosphatase signaling. This function resulted from a direct interaction between SIRPα and CD18 (β2 integrin) in “ cis ” at the surface of macrophages, involving SIRPα amino acids distinct from those implicated in the SIRPα-CD47 interaction. The cis interaction prevented activation of CD18, which is necessary for phagocytosis. Combined blockade of SIRPα-CD18 and SIRPα-CD47 was essential for maximizing phagocytosis and suppression of tumor growth in vivo . Similar cis interactions between CD18 and other inhibitory checkpoints, including PD-1, were also observed. Thus, in addition to mediating effects when engaged by ligands in trans , inhibitory checkpoints suppress immune cell activation through a mechanism targeting CD18 in cis . This dual mode of action should be considered when developing blockers of inhibitory checkpoints for immunotherapy.