Tang et al. uncovered a new mechanism of CD47-mediated suppression of phagocytosis. In addition to SIRPα engagement on macrophages, CD47 suppressed phagocytosis and antitumor immunity by masking target cell-intrinsic pro-phagocytic ligand SLAMF7. CD47 interaction with SLAMF7 in cis on tumor cells prevented the homotypic trans interaction of SLAMF7 on tumor cells with SLAMF7 on macrophages and suppressed phagocytosis. CD47 blockade or a first-in-class SLAMF7 monoclonal antibody Z10, but not SIRPα blockade, freed SLAMF7 from CD47 and promoted phagocytosis, suggesting novel, potentially safer, opportunities for treatment.
Contributed by Shishir Pant
ABSTRACT: Cancer cells often overexpress CD47, which triggers the inhibitory receptor SIRPα expressed on macrophages, to elude phagocytosis and antitumor immunity. Pharmacological blockade of CD47 or SIRPα is showing promise as anticancer therapy, although CD47 blockade has been associated with hematological toxicities that may reflect its broad expression pattern on normal cells. Here we found that, in addition to triggering SIRPα, CD47 suppressed phagocytosis by a SIRPα-independent mechanism. This mechanism prevented phagocytosis initiated by the pro-phagocytic ligand, SLAMF7, on tumor cells, due to a cis interaction between CD47 and SLAMF7. The CD47-SLAMF7 interaction was disrupted by CD47 blockade and by a first-in-class agonist SLAMF7 antibody, but not by SIRPα blockade, thereby promoting antitumor immunity. Hence, CD47 suppresses phagocytosis not only by engaging SIRPα, but also by masking cell-intrinsic pro-phagocytic ligands on tumor cells and knowledge of this mechanism may influence the decision between CD47 blockade or SIRPα blockade for therapeutic purposes.
Author Info: (1) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Qubec, Canada. (2) Laboratory of Molecular Oncology, Institut de recherches cl
Author Info: (1) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Qubec, Canada. (2) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Qubec, Canada. (3) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Qubec, Canada. (4) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Qubec, Canada. Department of Medicine, McGill University, Montral, Qubec, Canada. (5) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Qubec, Canada. (6) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Qubec, Canada. Department of Medicine, McGill University, Montral, Qubec, Canada. (7) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA. (8) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA. (9) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Qubec, Canada. andre.veillette@ircm.qc.ca. Department of Medicine, McGill University, Montral, Qubec, Canada. andre.veillette@ircm.qc.ca. Department of Medicine, University of Montral, Montral, Qubec, Canada. andre.veillette@ircm.qc.ca.
