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

Cell. 2015 May 21;161(5):1035-1045. doi: 10.1016/j.cell.2015.04.016. Epub 2015 May 11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / immunology*
  • Antibody-Dependent Cell Cytotoxicity
  • Antigen Presentation
  • CD11c Antigen / immunology
  • Cancer Vaccines / immunology
  • Disease Models, Animal
  • Humans
  • Macrophages / immunology
  • Mice
  • Neoplasms / immunology*
  • Receptors, IgG / immunology*

Substances

  • Antibodies, Monoclonal
  • CD11c Antigen
  • Cancer Vaccines
  • Receptors, IgG