Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis

Roarke A. Kamber, Yoko Nishiga, Bhek Morton, Allison M. Banuelos, Amira A. Barkal, Felipe Vences-Catalán, Mingxin Gu, Daniel Fernandez, Jose A. Seoane, David Yao, Katherine Liu, Sijie Lin, Kaitlyn Spees, Christina Curtis, Livnat Jerby-Arnon, Irving L. Weissman, Julien Sage and Michael C. Bassik ()
Additional contact information
Roarke A. Kamber: Stanford University School of Medicine
Yoko Nishiga: Stanford University School of Medicine
Bhek Morton: Stanford University School of Medicine
Allison M. Banuelos: Stanford University School of Medicine
Amira A. Barkal: Stanford University School of Medicine
Felipe Vences-Catalán: Stanford University School of Medicine
Mingxin Gu: Stanford University School of Medicine
Daniel Fernandez: Stanford University
Jose A. Seoane: Stanford University School of Medicine
David Yao: Stanford University School of Medicine
Katherine Liu: Stanford University School of Medicine
Sijie Lin: Stanford University School of Medicine
Kaitlyn Spees: Stanford University School of Medicine
Christina Curtis: Stanford University School of Medicine
Livnat Jerby-Arnon: Stanford University School of Medicine
Irving L. Weissman: Stanford University School of Medicine
Julien Sage: Stanford University School of Medicine
Michael C. Bassik: Stanford University School of Medicine

Nature, 2021, vol. 597, issue 7877, 549-554

Abstract: Abstract Monoclonal antibody therapies targeting tumour antigens drive cancer cell elimination in large part by triggering macrophage phagocytosis of cancer cells1–7. However, cancer cells evade phagocytosis using mechanisms that are incompletely understood. Here we develop a platform for unbiased identification of factors that impede antibody-dependent cellular phagocytosis (ADCP) using complementary genome-wide CRISPR knockout and overexpression screens in both cancer cells and macrophages. In cancer cells, beyond known factors such as CD47, we identify many regulators of susceptibility to ADCP, including the poorly characterized enzyme adipocyte plasma membrane-associated protein (APMAP). We find that loss of APMAP synergizes with tumour antigen-targeting monoclonal antibodies and/or CD47-blocking monoclonal antibodies to drive markedly increased phagocytosis across a wide range of cancer cell types, including those that are otherwise resistant to ADCP. Additionally, we show that APMAP loss synergizes with several different tumour-targeting monoclonal antibodies to inhibit tumour growth in mice. Using genome-wide counterscreens in macrophages, we find that the G-protein-coupled receptor GPR84 mediates enhanced phagocytosis of APMAP-deficient cancer cells. This work reveals a cancer-intrinsic regulator of susceptibility to antibody-driven phagocytosis and, more broadly, expands our knowledge of the mechanisms governing cancer resistance to macrophage phagocytosis.

Date: 2021
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DOI: 10.1038/s41586-021-03879-4

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