Abstract
SLAMF7 expression is required for macrophage-mediated phagocytosis of hematopoietic tumor cells.
Major finding: SLAMF7 expression is required for macrophage-mediated phagocytosis of hematopoietic tumor cells.
Mechanism: SLAMF7 interacts with the integrin Mac-1 on macrophages to promote phagocytosis.
Impact: SIRPα–CD47 blockade may be most effective in patients with hematologic cancers that express SLAMF7.
Tumor cell phagocytosis by macrophages can be enhanced by therapeutic blockade of the signal regulatory protein-α (SIRPα) inhibitory receptor or its ligand CD47. However, prophagocytic receptors remain largely unknown, prompting Chen and colleagues to test bone marrow–derived macrophages for their ability to phagocytose various target cells. SIRPα–CD47 blockade with anti-CD47 enhanced phagocytosis of a subset of hematopoietic tumor cells (including B-cell lineage and myeloid tumor cell lines), but not of nonhematopoietic tumor cells. Based on these findings, the involvement of the SLAM family of receptors, which are expressed only on hematopoietic cells, was evaluated. Macrophages from mice lacking the SLAM receptors did not display increased phagocytic activity in response to SIRPα–CD47 blockade, and, specifically, SLAMF7 expression on macrophages and tumor cells was both necessary and sufficient for hematopoietic cell phagocytosis. SLAMF7 acted independently of the SAP adaptor proteins to promote phagocytosis. Further, SLAMF7-dependent phagocytosis required expression of two immunoreceptor tyrosine-based activation motif (ITAM)–containing proteins, DAP12 and FcRγ, which interact with the integrin Mac-1 and mediate immune cell activation via the SRC, SYK, and BTK kinases, and SLAMF7 interacted with macrophage Mac-1 to facilitate phagocytosis. Analysis of gene expression data revealed that some hematologic cancers, including chronic lymphocytic leukemia, myelodysplastic syndrome, multiple myeloma, and diffuse large B-cell lymphoma, frequently display high levels of both SLAMF7 and CD47, suggesting that patients with these cancers may be sensitive to SIRPα–CD47 blockade. The identification of SLAMF7 as a prophagocytic receptor elucidates a mechanism by which macrophages selectively target hematopoietic cells, and suggests that patients with SLAMF7-positive tumors may be most likely to respond to SIRPα–CD47 blockade.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.