Inflammatory macrophages exploit unconventional pro-phagocytic integrins for phagocytosis and anti-tumor immunity
Zhenghai Tang,
Dominique Davidson,
Rui Li,
Ming-Chao Zhong,
Jin Qian,
Jun Chen,
André Veillette
Affiliations
Zhenghai Tang
Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
Dominique Davidson
Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
Rui Li
Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Medicine, McGill University, Montréal, QC H3G 1Y6, Canada
Ming-Chao Zhong
Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
Jin Qian
Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
Jun Chen
Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; Corresponding author
André Veillette
Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Medicine, McGill University, Montréal, QC H3G 1Y6, Canada; Department of Medicine, University of Montréal, Montréal, QC H3C 3J7, Canada; Corresponding author
Summary: Blockade of the inhibitory checkpoint SIRPα-CD47 promotes phagocytosis of cancer cells by macrophages and is a promising avenue in anti-cancer therapy. Productive phagocytosis is strictly predicated on co-engagement of pro-phagocytic receptors—namely, Fc receptors (FcRs), integrin CD11b, or SLAMF7—by their ligands on cancer cells. Here, we examine whether additional pro-phagocytic receptors could be harnessed to broaden the scope of phagocytosis. Inflammatory stimuli, including multiple cytokines and Toll-like receptor (TLR) ligands, augment phagocytosis efficiency and fully alleviate the requirement of FcRs, CD11b, and SLAMF7 for phagocytosis. These effects are mediated by the unconventional pro-phagocytic integrins CD11a and CD11c, which act with CD18 to initiate actin polarization, leading to phagocytosis. Some inflammatory stimuli enable phagocytosis even in the absence of SIRPα-CD47 blockade. Higher CD11c expression in macrophage-enriched tumors correlates with improved survival in clinical studies. Thus, inflammatory macrophages exploit unconventional pro-phagocytic integrins for improved phagocytosis and anti-tumor immunity.
