Expression of modified FcγRI enables myeloid cells to elicit robust tumor-specific cytotoxicity

Abstract

AbstractDespite the central role of T cells in tumor immunity, attempts to harness their cytotoxic capacity as a therapy have met limited efficacy, partially as a result of the suppressive microenvironment which limits their migration and activation. In contrast, myeloid cells massively infiltrate tumors and are well adapted to survive in these harsh conditions. While they are equipped with cell-killing abilities, they often adapt an immunosuppressive phenotype upon migration to tumors. Therefore, the questions of how to modify their activation programing against cancer, and what signaling cascades should be activated in myeloid cells to elicit their cytotoxicity has remained unclear.Here, we found that activation of IgM-induced signaling in myeloid cells results in secretion of lytic granules and massive tumor cell death. These findings open venues for designing novel immunotherapy by equipping monocytes with chimeric receptors that target tumor antigens and consequently, signal through IgM receptor. Nonetheless, we found that myeloid cells do not express the antibody-derived portion used to recognize the tumor antigen due to induction of an ER stress response. To overcome this limitation, we designed chimeric receptors that are based on the high affinity FcγRI for IgG. Incubation of macrophages transfected with these receptors along with tumor-binding IgG induced massive tumor cell killing and secretion of reactive oxygen species and Granzyme B.Overall, this work highlights the challenges involved in genetically reprograming the signaling in myeloid cells and provides a framework for endowing myeloid cells with antigen-specific cytotoxicity.