Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation

Suter, Emily C.; Schmid, Eva M.; Harris, Andrew R.; Voets, Erik; Francica, Brian; Fletcher, Daniel A.

doi:10.1016/j.celrep.2021.109587

Title: Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation

Journal Article · 23 August 2021 · Cell Reports

DOI: https://doi.org/10.1016/j.celrep.2021.109587 · OSTI ID:2470754

Suter, Emily C. ^[1]; Schmid, Eva M. ^[2];

^[3]; Voets, Erik ^[4]; Francica, Brian ^[5];

^[6]

University of California, Berkeley, CA (United States); University of California, San Francisco, CA (United States)
University of California, Berkeley, CA (United States)
University of California, Berkeley, CA (United States); Carleton University, Ottawa, ON (Canada)
Aduro Biotech Europe, Oss (Netherlands)
Aduro Biotech Inc., Emeryville, CA (United States)
University of California, Berkeley, CA (United States); University of California, San Francisco, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Chan Zuckerberg Biohub, San Francisco, CA (United States)

Cancer immunotherapies often modulate macrophage effector function by introducing either targeting antibodies that activate Fcγ receptors (FcγRs) or blocking antibodies that disrupt inhibitory SIRPα-CD47 engagement. However, how these competing signals are integrated is poorly understood, raising questions about how to effectively titrate immune responses. Here, we find that macrophage phagocytic decisions are regulated by the ratio of activating ligand to inhibitory ligand over a broad range of absolute molecular densities. Using both endogenous and chimeric receptors, we show that activating:inhibitory ligand ratios of at least 10:1 are required to promote phagocytosis of model antibody-opsonized CD47-inhibited targets and that lowering that ratio reduces FcγR phosphorylation because of inhibitory phosphatases recruited to CD47-bound SIRPα. We demonstrate that ratiometric signaling is critical for phagocytosis of tumor cells and can be modified by blocking SIRPα, indicating that balancing targeting and blocking antibodies may be important for controlling macrophage phagocytosis in cancer immunotherapy.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF); USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2470754

Journal Information:: Cell Reports, Journal Name: Cell Reports Journal Issue: 8 Vol. 36; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
CD47
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ITIM
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cell biology
checkpoint blockade
macrophage
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Title: Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation

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