Uncovering the key mediators of monocyte trogocytosis of cancer cells and implications on monocyte function, antibody efficacy and antigen presentation 4363

Abstract Description Myeloid cells play a central role in modulating immune response to cancer and have been linked to clinical outcomes in patients with solid tumors including nonresponse to immunotherapy. As such, there is a need to investigate their functionality in the tumor to identify new mechanisms of immune modulation for therapeutic benefit. We have found trogocytosis, a poorly understood cell-cell interaction mechanism, to be a prominent antibody-enhanced mode of monocyte-tumor cell communication across several aggressive cancer cell lines. The mechanistic processes governing monocyte trogocytosis of tumor cells and their effect on monocyte activation are largely unexplored. In this study, we leveraged functional analyses to interrogate the signaling pathways driving and resulting from monocyte trogocytosis of tumor cells. Both genome-wide and a targeted CRISPR/Cas9 screen identified Rho GTPase signaling as a significant regulator of trogocytosis by monocytes. Concordantly, transcriptomic analysis revealed an upregulation of integrin response and Rho GTPase signaling in trogocytic monocytes. Trogocytic monocytes also displayed higher expression of MHC II and complement related genes, suggesting an activation of antigen presentation machinery and inflammatory response. These results elucidate monocyte trogocytic function and targetable regulators that provide new insights into myeloid biology in disease and actionable avenues to impact antigen presentation and antibody modes of function. Funding Sources Suported by NIH-Oxford/Cambridge Scholars Program; US NIH ZIA BC 011332 and ZIA BC 011855; and NCI Cancer Moonshot. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)