Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation
| Autor: | Eva M. Schmid, Daniel A. Fletcher, Emily C. Suter, Andrew R. Harris, Erik Voets, Brian Francica |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_treatment
Medical Physiology Fc receptor Cancer immunotherapy ITAM Neoplasms Receptors Macrophage Phosphorylation Biology (General) Receptor CD47 Cancer biology Chemistry phagocytosis Ligand (biochemistry) Cell biology Blocking therapeutic antibody Biotechnology IgG QH301-705.5 1.1 Normal biological development and functioning Phagocytosis CD47 Antigen macrophage General Biochemistry Genetics and Molecular Biology Antibodies Article Vaccine Related Underpinning research Blocking antibody SIRPα medicine Animals Antibodies Blocking cancer immunotherapy Inflammatory and immune system Receptors IgG ITIM biology.protein checkpoint blockade Immunization Biochemistry and Cell Biology Carrier Proteins |
| Zdroj: | Cell Reports, Vol 36, Iss 8, Pp 109587-(2021) Cell reports Cell reports, vol 36, iss 8 |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY 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. In brief Suter et al. use reconstituted cell-like particles to quantitatively probe how macrophages integrate simultaneous signals from activating Fc receptors and inhibitory SIRPα. The authors show that the ratio of antibody:CD47 on the target changes relative enrichment of competing Syk kinase and SHP1 phosphatase at the interface, ultimately dictating phagocytosis. Graphical Abstract |
| Databáze: | OpenAIRE |
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