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Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis

Roarke A Kamber1, Yoko Nishiga1,2,3, Bhek Morton1

  • 1Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Nature
|September 9, 2021
PubMed

Insights

Researchers identified adipocyte plasma membrane-associated protein (APMAP) as a key factor enabling cancer cells to evade macrophage phagocytosis. Loss of APMAP enhances cancer cell elimination by immunotherapy, offering new therapeutic strategies.

Area of Science:

  • Immunology
  • Cancer Biology
  • Genetics

Background:

  • Monoclonal antibody therapies eliminate cancer cells by stimulating macrophage phagocytosis.
  • Cancer cells possess incompletely understood mechanisms to evade phagocytosis, limiting therapeutic efficacy.

Purpose of the Study:

  • To identify novel factors that regulate cancer cell susceptibility to antibody-dependent cellular phagocytosis (ADCP).
  • To uncover mechanisms of cancer cell resistance to phagocytosis mediated by macrophages.

Main Methods:

  • Development of a platform for unbiased, genome-wide CRISPR knockout and overexpression screens in cancer cells and macrophages.
  • Identification of ADCP regulators using complementary screening approaches.

Main Results:

  • Adipocyte plasma membrane-associated protein (APMAP) was identified as a novel regulator of ADCP in cancer cells.
  • Loss of APMAP significantly enhanced phagocytosis of various cancer cells, including ADCP-resistant types, when combined with tumor antigen-targeting or CD47-blocking antibodies.
  • APMAP loss synergized with tumor-targeting monoclonal antibodies to inhibit tumor growth in vivo.
  • G-protein-coupled receptor GPR84 was found to mediate enhanced phagocytosis of APMAP-deficient cancer cells by macrophages.

Conclusions:

  • APMAP is a cancer-intrinsic factor that promotes resistance to antibody-driven phagocytosis.
  • Targeting APMAP presents a promising strategy to overcome cancer cell evasion and enhance immunotherapy effectiveness.
  • This study expands the understanding of macrophage phagocytosis regulation and cancer immune evasion mechanisms.

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