title: Differential Fc-Receptor Engagement Drives an Anti-tumor Vaccinal Effect.
abstract: Passively administered anti-tumor monoclonal antibodies (mAbs) rapidly kill tumor targets via FcγR-mediated cytotoxicity (ADCC), a short-term process. However, anti-tumor mAb treatment can also induce a vaccinal effect, in which mAb-mediated tumor death induces a long-term anti-tumor cellular immune response. To determine how such responses are generated, we utilized a murine model of an anti-tumor vaccinal effect against a model neoantigen. We demonstrate that FcγR expression by CD11c(+) antigen-presenting cells is required to generate anti-tumor T cell responses upon ADCC-mediated tumor clearance. Using FcγR-humanized mice, we demonstrate that anti-tumor human (h)IgG1 must engage hFcγRIIIA on macrophages to mediate ADCC, but also engage hFcγRIIA, the sole hFcγR expressed by human dendritic cells (DCs), to generate a potent vaccinal effect. Thus, while next-generation anti-tumor antibodies with enhanced binding to only hFcγRIIIA are now in clinical use, ideal anti-tumor antibodies must be optimized for both cytotoxic effects as well as hFcγRIIA engagement on DCs to stimulate long-term anti-tumor cellular immunity.
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: DiLillo
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: ravetch@rockefeller.edu.
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D017951:Antigen Presentation; D039521:CD11c Antigen / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D008264:Macrophages / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D039521:CD11c Antigen; D019496:Cancer Vaccines; D017452:Receptors, IgG