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

The identification of homotypic SLAMF7 interactions responsible for haematopoietic tumour cell phagocytosis by macrophages when the inhibitory receptor/ligand interaction of SIRPα/CD47 is blocked therapeutically. SLAMF7 receptor aids blockade therapy Phagocytosis of tumour cells has a critical role in cancer control, but the pro-phagocytic receptors responsible for this process are largely unknown. André Veillette and colleagues identify homotypic SLAMF7 interactions that are responsible for phagocytosis of haematopoietic tumour cells by macrophages when the inhibitory receptor–ligand interaction of CD47–SIRPα is blocked therapeutically. The authors suggest that the presence of SLAMF7 receptors on haematopoietic tumours could therefore be an important factor in blockade therapy. Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors 1 , 2 . Phagocytosis by macrophages plays a critical role in cancer control 3 , 4 , 5 , 6 . 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 7 , 8 , 9 , 10 , suggesting that blockade of the SIRPα–CD47 checkpoint could be useful in treating human cancer 11 , 12 , 13 , 14 . 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 15 , 16 , 17 , 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 21 ,