Dual role of Fc Receptor-triggered trogocytosis mediated by human tumor-infiltrating macrophages and neutrophils in the regulation of anti-tumor antibody efficacy 3084

Abstract Description The clinical benefits of tumor-targeting antibodies (tAb) are modest in solid human tumors. The efficacy of many tAbs is dependent on Fc receptor (FcR)–expressing leukocytes that bind Fc fragments of tAb. Tumor-associated macrophages (TAM) and neutrophils (TAN) represent the majority of FcR+ effectors in solid tumors. A better understanding of the mechanisms by which TAN and TAM regulate tAb response could help improve the efficacy of tAbs. Here, we found that myeloid effectors interacting with tAb-opsonized cancer cells used antibody-dependent trogocytosis (ADT). During this process, myeloid cells “nibble off” tumor cell fragments containing tAb/targeted antigen (tAg) complexes. ADT is only tumoricidal when tumor cells express high levels of tAg and effectors are present at high effector-to-tumor ratios. If neither of these conditions are met, which is typical for solid tumors, ADT is sublethal. Sublethal ADT, mainly mediated by TAM, leads to two outcomes: (i) removal of surface tAg/tAb complexes from the tumor surface thereby facilitating tumor cell escape; and (ii) acquisition of bystander tAgs by TAM with subsequent cross-presentation and stimulation of tumor-specific T-cell responses. TAN stimulate tumor cell growth in the presence of IgG1 tAb; however, IgA tAbs trigger the tumoricidal activity and negate the stimulatory effect of TAN. Overall, this study provides mechanistic insight by which myeloid effectors mediate tumor cell killing and resistance during tAb therapy Funding Sources This work was supported by the NIH/NCI RO1 CA187392–01 and Janssen Pharmaceuticals Inc. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)