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CD47 masks pro-phagocytic ligands in cis on tumor cells to suppress antitumor immunity

Zhenghai Tang1, Ming-Chao Zhong1, Jin Qian1

  • 1Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec, Canada.

Nature Immunology
|November 9, 2023
PubMed

Insights

Cancer cells use CD47 to evade immune cells. Researchers discovered CD47 also blocks phagocytosis independently of SIRPα, offering new therapeutic strategies beyond CD47 or SIRPα blockade.

Area of Science:

  • Immunology
  • Cancer Biology
  • Drug Discovery

Background:

  • Cancer cells overexpress CD47, inhibiting macrophages via SIRPα to evade immune detection and phagocytosis.
  • CD47 blockade is a promising cancer therapy, but potential hematological toxicities arise from CD47's broad expression on normal cells.

Purpose of the Study:

  • To investigate the mechanisms by which CD47 suppresses phagocytosis beyond its interaction with SIRPα.
  • To explore novel therapeutic targets for enhancing antitumor immunity by understanding CD47's multifaceted role.

Main Methods:

  • Investigated the interaction between CD47 and the pro-phagocytic ligand SLAMF7 on tumor cells.
  • Assessed the impact of CD47 blockade and SLAMF7 agonist antibodies on phagocytosis.
  • Compared the efficacy of CD47 blockade, SIRPα blockade, and SLAMF7 agonism in promoting antitumor immunity.

Main Results:

  • Discovered a SIRPα-independent mechanism where CD47 directly suppresses phagocytosis by interacting with SLAMF7 in cis.
  • Demonstrated that CD47 blockade and a SLAMF7 agonist antibody disrupt the CD47-SLAMF7 interaction, enhancing phagocytosis.
  • Showed that SIRPα blockade does not affect the CD47-SLAMF7 interaction, highlighting a distinct pathway.

Conclusions:

  • CD47 employs both SIRPα-dependent and SIRPα-independent mechanisms, including masking SLAMF7, to inhibit phagocytosis.
  • Targeting the CD47-SLAMF7 interaction with SLAMF7 agonist antibodies offers a potential therapeutic strategy with a different toxicity profile than CD47 blockade.
  • Understanding these distinct mechanisms can guide the selection of optimal immunotherapies, such as CD47 blockade versus SIRPα blockade or SLAMF7 agonism.

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