
Activation of IgM receptor signaling in myeloid cells induces massive tumor cell killing through secretion of lytic granules and reactive oxygen species. Overcoming the challenge of expressing antibody-derived tumor antigen recognition domains in myeloid cells, a novel chimeric Fc receptor design enables antigen-specific tumor cell lysis by myeloid cells.


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Despite 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 these harsh conditions. While they are equipped with cell-killing abilities, they often adopt an immunosuppressive phenotype upon migration to tumors. Therefore, the questions of how to modify their activation programming against cancer, and what signaling cascades should be activated in myeloid cells to elicit their cytotoxicity have 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 the 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 expressing 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 reprogramming the signaling in myeloid cells and provides a framework for endowing myeloid cells with antigen-specific cytotoxicity.

### Competing Interest Statement

This work has been supported by Gilboa Therapeutics, of which YC, PR, and DR are shareholders. All other authors have declared that no conflict of interest exists.

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

harnessing-myeloid-cell-cytotoxicity-through-engineered-fc-receptor-signaling-for-tumor-immunotherapy


Harnessing Myeloid Cell Cytotoxicity through Engineered Fc Receptor Signaling for Tumor Immunotherapy


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변형된 FcγRI 발현을 통해 골수세포가 강력한 종양 특이적 세포독성을 발휘할 수 있다.


종양-특이적-세포독성을-유도하기-위한-변형된-fcγri의-발현


종양 특이적 세포독성을 유도하기 위한 변형된 FcγRI의 발현
