They also reveal a novel SAP adaptor-independent function for a SLAM receptor. These findings elucidate the mechanism by which macrophages engulf and destroy haematopoietic tumour cells.
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, 22.
In contrast to most SLAM receptor functions 15, 16, 17, SLAMF7-mediated phagocytosis was independent of signalling lymphocyte activation molecule-associated protein (SAP) adaptors. 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. 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. 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. However, the pro-phagocytic receptor(s) responsible for tumour cell phagocytosis is(are) largely unknown. 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. Phagocytosis by macrophages plays a critical role in cancer control 3, 4, 5, 6. Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors 1, 2.
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