Differential Fc-Receptor Engagement Drives an Anti-tumor Vaccinal Effect.

ABSTRACT: Passively administered anti-tumor monoclonal antibodies (mAbs) rapidly kill tumor targets via Fc?R-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 Fc?R expression by CD11c(+) antigen-presenting cells is required to generate anti-tumor T cell responses upon ADCC-mediated tumor clearance. Using Fc?R-humanized mice, we demonstrate that anti-tumor human (h)IgG1 must engage hFc?RIIIA on macrophages to mediate ADCC, but also engage hFc?RIIA, the sole hFc?R expressed by human dendritic cells (DCs), to generate a potent vaccinal effect. Thus, while next-generation anti-tumor antibodies with enhanced binding to only hFc?RIIIA are now in clinical use, ideal anti-tumor antibodies must be optimized for both cytotoxic effects as well as hFc?RIIA engagement on DCs to stimulate long-term anti-tumor cellular immunity.

SUBMITTER: DiLillo DJ 

PROVIDER: S-EPMC4441863 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature