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Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation

Emily C Suter1, Eva M Schmid2, Andrew R Harris3

  • 1Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA; UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA, USA.

Cell Reports
|August 25, 2021
PubMed

Insights

Macrophage phagocytosis decisions in cancer immunotherapy depend on the ratio of activating to inhibitory signals, not just absolute levels. A 10:1 activating to inhibitory ligand ratio is crucial for effective tumor cell clearance.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cellular Signaling

Background:

  • Cancer immunotherapies leverage macrophages by modulating Fcγ receptors (FcγRs) and SIRPα-CD47 interactions.
  • The integration of competing activating and inhibitory signals in macrophages remains poorly understood.
  • Effective titration of immune responses in immunotherapy requires understanding signal integration.

Purpose of the Study:

  • To investigate how macrophages integrate competing activating (FcγR) and inhibitory (SIRPα-CD47) signals.
  • To determine the critical ratio of activating to inhibitory ligands for macrophage phagocytosis.
  • To explore the implications of ratiometric signaling for cancer immunotherapy.

Main Methods:

  • Utilized endogenous and chimeric receptors to model macrophage activation.
  • Quantified phagocytosis of antibody-opsonized targets with varying ligand densities.
  • Assessed FcγR phosphorylation and phosphatase recruitment in response to ligand engagement.

Main Results:

  • Macrophage phagocytic activity is governed by the ratio of activating to inhibitory ligands, not absolute densities.
  • An activating to inhibitory ligand ratio of at least 10:1 is necessary for phagocytosis of CD47-inhibited targets.
  • Lower ratios reduce FcγR phosphorylation due to inhibitory phosphatases recruited by SIRPα-CD47.

Conclusions:

  • Ratiometric signaling is critical for macrophage-mediated phagocytosis of tumor cells.
  • Modulating SIRPα signaling can alter phagocytic responses.
  • Balancing targeting and blocking antibodies is essential for optimizing macrophage phagocytosis in cancer immunotherapy.
Keywords:
CD47Fc receptorITAMITIMSIRPαcancer immunotherapycheckpoint blockademacrophagephagocytosistherapeutic antibody

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