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Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis

Author

Listed:
  • Roarke A. Kamber

    (Stanford University School of Medicine)

  • Yoko Nishiga

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Bhek Morton

    (Stanford University School of Medicine)

  • Allison M. Banuelos

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Amira A. Barkal

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University)

  • Felipe Vences-Catalán

    (Stanford University School of Medicine)

  • Mingxin Gu

    (Stanford University School of Medicine)

  • Daniel Fernandez

    (Stanford University
    Stanford University)

  • Jose A. Seoane

    (Stanford University School of Medicine
    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
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Livnat Jerby-Arnon

    (Stanford University School of Medicine
    Chan Zuckerberg Biohub)

  • Irving L. Weissman

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Julien Sage

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University)

  • Michael C. Bassik

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University)

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.

Suggested Citation

  • 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 &, 2021. "Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis," Nature, Nature, vol. 597(7877), pages 549-554, September.
  • Handle: RePEc:nat:nature:v:597:y:2021:i:7877:d:10.1038_s41586-021-03879-4
    DOI: 10.1038/s41586-021-03879-4
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    Citations

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    Cited by:

    1. Chih-Wei Chou & Chia-Nung Hung & Cheryl Hsiang-Ling Chiu & Xi Tan & Meizhen Chen & Chien-Chin Chen & Moawiz Saeed & Che-Wei Hsu & Michael A. Liss & Chiou-Miin Wang & Zhao Lai & Nathaniel Alvarez & Paw, 2023. "Phagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Jinhu Liu & Huajun Zhao & Tong Gao & Xinyan Huang & Shujun Liu & Meichen Liu & Weiwei Mu & Shuang Liang & Shunli Fu & Shijun Yuan & Qinglin Yang & Panpan Gu & Nan Li & Qingping Ma & Jie Liu & Xinke Zh, 2024. "Glypican-3-targeted macrophages delivering drug-loaded exosomes offer efficient cytotherapy in mouse models of solid tumours," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Jianting Shi & Xun Wu & Ziyi Wang & Fang Li & Yujiao Meng & Rebecca M. Moore & Jian Cui & Chenyi Xue & Katherine R. Croce & Arif Yurdagul & John G. Doench & Wei Li & Konstantinos S. Zarbalis & Ira Tab, 2022. "A genome-wide CRISPR screen identifies WDFY3 as a regulator of macrophage efferocytosis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Xuan Zhang & Yujing Wang & Shreyas Supekar & Xu Cao & Jingkai Zhou & Jessica Dang & Siqi Chen & Laura Jenkins & Sara Marsango & Xiu Li & Guibing Liu & Graeme Milligan & Mingye Feng & Hao Fan & Weimin , 2023. "Pro-phagocytic function and structural basis of GPR84 signaling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Nathan M. Belliveau & Matthew J. Footer & Emel Akdoǧan & Aaron P. Loon & Sean R. Collins & Julie A. Theriot, 2023. "Whole-genome screens reveal regulators of differentiation state and context-dependent migration in human neutrophils," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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