Abstract
Abstract Phagocytosis of specific targets in clinically-relevant settings, including engulfment of tumor cells and removal of cell corpses following aggressive cancer treatment, has been hampered by an incomplete understanding of phagocytic signaling. Therefore, we developed a cellular reconstitution platform amenable to direct, real-time imaging to dissect phagocytic signaling in molecular detail. Our gain-of-function system converts inept phagocytes into efficient ones, enabling us to appreciate the signaling behaviors associated with phagocytic proficiency. We report that 1) phagocytosis receptors form mobile microclusters in response to ligation, 2) microclusters recruit cytosolic collaborators to the plasma membrane and spatially organize actin dynamics at the phagocytic synapse, and 3) the natural ligand-receptor pair can be replaced by an engineered module, indicating that phagocytic signaling can be reprogrammed towards specific targets. Thus, we have discovered that a conserved signaling system required for recognition and removal of altered self bears unexpected mechanistic similarity to adaptive immune responses directed towards pathogens and tumor cells. In addition, our ability to replace the endogenous receptor with a heterologous system indicates that phagocytosis can be programmed in a manner conceptually similar to the Chimeric Antigen Receptor used in the clinic to program cytotoxic T cells to kill tumor cells. Our ability to engineer the process suggests that methods to re-direct phagocytes towards targets of clinical importance are possible, approaches that may enable recognition and removal of tumor cells and boost the anti-tumor immune response. Citation Format: Adam Williamson, Ron Vale. Engineering phagocytic signaling [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr PR15.
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