SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin

Nature. 2017 Apr 27;544(7651):493-497. doi: 10.1038/nature22076. Epub 2017 Apr 19.


Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors. Phagocytosis by macrophages plays a critical role in cancer control. Therapeutic blockade of signal regulatory protein (SIRP)-α, an inhibitory receptor on macrophages, or of its ligand CD47 expressed on tumour cells, improves tumour cell elimination in vitro and in vivo, suggesting that blockade of the SIRPα-CD47 checkpoint could be useful in treating human cancer. However, the pro-phagocytic receptor(s) responsible for tumour cell phagocytosis is(are) largely unknown. Here we find that macrophages are much more efficient at phagocytosis of haematopoietic tumour cells, compared with non-haematopoietic tumour cells, in response to SIRPα-CD47 blockade. Using a mouse lacking the signalling lymphocytic activation molecule (SLAM) family of homotypic haematopoietic cell-specific receptors, we determined that phagocytosis of haematopoietic tumour cells during SIRPα-CD47 blockade was strictly dependent on SLAM family receptors in vitro and in vivo. In both mouse and human cells, this function required a single SLAM family member, SLAMF7 (also known as CRACC, CS1, CD319), expressed on macrophages and tumour cell targets. In contrast to most SLAM receptor functions, SLAMF7-mediated phagocytosis was independent of signalling lymphocyte activation molecule-associated protein (SAP) adaptors. Instead, it depended on the ability of SLAMF7 to interact with integrin Mac-1 (refs 18, 19, 20) and utilize signals involving immunoreceptor tyrosine-based activation motifs. These findings elucidate the mechanism by which macrophages engulf and destroy haematopoietic tumour cells. They also reveal a novel SAP adaptor-independent function for a SLAM receptor. Lastly, they suggest that patients with tumours expressing SLAMF7 are more likely to respond to SIRPα-CD47 blockade therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Antigens, Differentiation / immunology
  • Antigens, Differentiation / metabolism
  • CD47 Antigen / immunology
  • CD47 Antigen / metabolism
  • Female
  • Hematologic Neoplasms / drug therapy
  • Hematologic Neoplasms / immunology*
  • Hematologic Neoplasms / pathology*
  • Humans
  • Macrophage-1 Antigen / metabolism*
  • Macrophages / cytology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Phagocytosis / immunology*
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism
  • Signaling Lymphocytic Activation Molecule Family / deficiency
  • Signaling Lymphocytic Activation Molecule Family / metabolism*


  • Actins
  • Antigens, Differentiation
  • CD47 Antigen
  • CD47 protein, human
  • Macrophage-1 Antigen
  • Receptors, Immunologic
  • SIRPA protein, human
  • SLAMF7 protein, human
  • Signaling Lymphocytic Activation Molecule Family
  • Slamf7 protein, mouse