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

被引:227
作者
DiLillo, David J. [1 ]
Ravetch, Jeffrey V. [1 ]
机构
[1] Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10065 USA
关键词
IN-VIVO; ANTI-CD20; ANTIBODY; ADAPTIVE IMMUNITY; GAMMA RECEPTORS; DENDRITIC CELLS; TUMOR-IMMUNITY; MOUSE MODEL; CANCER; IMMUNOTHERAPY; RITUXIMAB;
D O I
10.1016/j.cell.2015.04.016
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Passively administered anti-tumor monoclonal antibodies (mAbs) rapidly kill tumor targets via Fc gamma 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 gamma R expression by CD11c(+) antigen-presenting cells is required to generate antitumor T cell responses upon ADCC-mediated tumor clearance. Using Fc gamma R-humanized mice, we demonstrate that anti-tumor human (h)IgG1 must engage hFc gamma RIIIA on macrophages to mediate ADCC, but also engage hFc gamma RIIA, the sole hFc gamma R expressed by human dendritic cells (DCs), to generate a potent vaccinal effect. Thus, while next-generation antitumor antibodies with enhanced binding to only hFc gamma RIIIA are now in clinical use, ideal anti-tumor antibodies must be optimized for both cytotoxic effects as well as hFc gamma RIIA engagement on DCs to stimulate long-term anti-tumor cellular immunity.
引用
收藏
页码:1035 / 1045
页数:11
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