An Fcγ Receptor-Dependent Mechanism Drives Antibody-Mediated Target-Receptor Signaling in Cancer Cells

Antibodies to cell-surface antigens trigger activatory Fc gamma receptor (Fc gamma R)-mediated retrograde signals in leukocytes to control immune effector functions. Here, we uncover an Fc gamma R mechanism that drives antibody-dependent forward signaling in target cells. Agonistic antibodies to death receptor 5 (DR5) induce cancer-cell apoptosis and are in clinical trials; however, their mechanism of action in vivo is not fully defined. Interaction of the DR5-agonistic antibody drozitumab with leukocyte Fc gamma Rs promoted DR5-mediated tumor-cell apoptosis. Whereas the anti-CD20 antibody rituximab required activatory Fc gamma Rs for tumoricidal function, drozitumab was effective in the context of either activatory or inhibitory Fc gamma Rs. A CD40-agonistic antibody required similar Fc gamma R interactions to stimulate nuclear factor-kappa B activity in B cells. Thus, Fc gamma Rs can drive antibody-mediated receptor signaling in target cells.