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Chimeric antigen receptors that trigger phagocytosis

Authors: Meghan A Morrissey; Adam P Williamson; Adriana M Steinbach; Edward W Roberts; Nadja Kern; Mark B Headley; Ronald D Vale;

Chimeric antigen receptors that trigger phagocytosis

Abstract

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 FcRγ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing macrophages reduce cancer cell number in co-culture by over 40%. Summary We report the first Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that promote engulfment of antigen-coated particles and cancer cells.

Country
United States
Keywords

Biomedical and clinical sciences, Immunological Synapses, receptors, Mice, Receptors, cell biology, 2.1 Biological and endogenous factors, Biology (General), Phosphorylation, Cancer, cancer biology, Cancer Biology, Tumor, Receptors, Chimeric Antigen, CD19, Q, R, phagocytosis, Gene Therapy, Silicon Dioxide, Microspheres, macrophages, Biological sciences, Medicine, Immunotherapy, signal transduction, Biotechnology, Signal Transduction, QH301-705.5, 1.1 Normal biological development and functioning, Science, Oncology and Carcinogenesis, Immunology, Antigens, CD19, 610, Fc Receptor, Cell Line, Phagocytosis, Antigens, Neoplasm, Cell Line, Tumor, Genetics, Animals, Humans, human, Antigens, mouse, Biomedical and Clinical Sciences, Inflammatory and immune system, Macrophages, Chimeric Antigen, Health sciences, NIH 3T3 Cells, Neoplasm, Immunization, Biochemistry and Cell Biology, Chimeric Antigen Receptor

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    selected citations
    These citations are derived from selected sources.
    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    235
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 0.1%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Top 10%
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 1%
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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
235
Top 0.1%
Top 10%
Top 1%
Green
gold