Tang et al. showed that phagocytosis suppression by Signal Regulatory Protein α (SIRPα) depends not only on trans CD47 binding and phosphatase signaling, but also on cis interactions with CD18 (β2 integrin) on the macrophage surface. Distinct SIRPα residues interacted with CD18 and CD47. SIRPα–CD18 interaction prevented Mac-1 (αMβ2, CD18/CD11b) activation, which is required for phagocytosis in synergy with the SIRPα–CD47 interaction. In mouse tumor models, treatment with anti-SIRPα bispecific Abs blocking both CD47 and CD18 interactions caused a greater increase in phagocytosis and antitumor activity than monospecific anti-SIRPα Abs.
Contributed by Paula Hochman
ABSTRACT: 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 (β2 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.
Author Info: (1) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Cancer Center, Faculty of Health Sciences, University of Macau, Macau S
Author Info: (1) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China. MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China. (2) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. (3) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. (4) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Department of Medicine, McGill University, Montral, Canada. (5) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Department of Medicine, McGill University, Montral, Canada. (6) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Department of Medicine, McGill University, Montral, Canada. (7) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. (8) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. (9) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Department of Medicine, McGill University, Montral, Canada. Department of Medicine, University of Montral, Montral, Canada.
