1. Cancer Biology
  2. Cell Biology

Chimeric antigen receptors that trigger phagocytosis

  1. Meghan A Morrissey
  2. Adam P Williamson
  3. Adriana M Steinbach
  4. Edward W Roberts
  5. Nadja Kern
  6. Mark B Headley
  7. Ronald Vale  Is a corresponding author
  1. University of California, San Francisco, United States
https://doi.org/10.7554/eLife.36688
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Cite this article
  1. Meghan A Morrissey
  2. Adam P Williamson
  3. Adriana M Steinbach
  4. Edward W Roberts
  5. Nadja Kern
  6. Mark B Headley
  7. Ronald Vale
(2018)
Chimeric antigen receptors that trigger phagocytosis
eLife 7:e36688.
https://doi.org/10.7554/eLife.36688
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Abstract

Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRɣ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole human cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing murine macrophages reduce cancer cell number in co-culture by over 40%.

Data availability

The replicates used to construct Figure 1d have been uploaded to Dryad (doi:10.5061/dryad.c57c1s0). Due to the large size of the datasets, the full set of raw images are available from the authors upon request.

The following data sets were generated

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Author details

  1. Meghan A Morrissey

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Adam P Williamson

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Adriana M Steinbach

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Edward W Roberts

    Department of Pathology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Nadja Kern

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Mark B Headley

    Department of Pathology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Ronald Vale

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    For correspondence
    Ron.Vale@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3460-2758

Funding

National Institute of General Medical Sciences (F32GM120990)

  • Meghan A Morrissey

Cancer Research Institute (Irvington Postdoctoral Fellowship)

  • Adam P Williamson

Howard Hughes Medical Institute

  • Ronald Vale

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice were maintained under specific pathogen-free conditions and treated in accordance with the regulatory standards of the NIH and American Association of Laboratory Animal Care standards, and are consistent with the UCSF Institution of Animal Care and Use Committee (IACUC approval: AN170208-01I).

Copyright

© 2018, Morrissey et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Meghan A Morrissey
  2. Adam P Williamson
  3. Adriana M Steinbach
  4. Edward W Roberts
  5. Nadja Kern
  6. Mark B Headley
  7. Ronald Vale
(2018)
Chimeric antigen receptors that trigger phagocytosis
eLife 7:e36688.
https://doi.org/10.7554/eLife.36688

Share this article

https://doi.org/10.7554/eLife.36688

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