期刊
CELL REPORTS
卷 37, 期 11, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.110111
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资金
- Canadian In-stitutes of Health Research [MT-14429, MOP-82906, FDN-143338]
- National Key R&D Program of China [2019YFA0110300, 2020YFA0509400]
- National Science Foundation of China [82071745]
- Bristol Myers Squibb
- Cole Foundation
The blockade of inhibitory checkpoint SIRPa-CD47 enhances phagocytosis of cancer cells by macrophages, and additional pro-phagocytic receptors, including unconventional integrins CD11a and CD11c, play a role in broadening the scope of phagocytosis, especially under inflammatory stimuli. These findings suggest that inflammatory macrophages exploit unconventional pro-phagocytic integrins for improved phagocytosis and anti-tumor immunity.
Blockade of the inhibitory checkpoint SIRPa-CD47 promotes phagocytosis of cancer cells by macrophages and is a promising avenue in anti-cancer therapy. Productive phagocytosis is strictly predicated on co-engagement of pro-phagocytic receptors-namely, Fc receptors (FcRs), integrin CD11b, or SLAMF7-by their ligands on cancer cells. Here, we examine whether additional pro-phagocytic receptors could be harnessed to broaden the scope of phagocytosis. Inflammatory stimuli, including multiple cytokines and Toll-like receptor (TLR) ligands, augment phagocytosis efficiency and fully alleviate the requirement of FcRs, CD11b, and SLAMF7 for phagocytosis. These effects are mediated by the unconventional pro-phagocytic integrins CD11a and CD11c, which act with CD18 to initiate actin polarization, leading to phagocytosis. Some inflammatory stimuli enable phagocytosis even in the absence of SIRPa-CD47 blockade. Higher CD11c expression in macrophage-enriched tumors correlates with improved survival in clinical studies. Thus, inflammatory macrophages exploit unconventional pro-phagocytic integrins for improved phagocytosis and anti-tumor immunity.
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