An Fcγ Receptor-Dependent Mechanism Drives Antibody-Mediated Target-Receptor Signaling in Cancer Cells
An Fcγ Receptor-Dependent Mechanism Drives Antibody-Mediated Target-Receptor Signaling in Cancer Cells
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DOI：
10.1016/j.ccr.2010.11.012
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发表时间：
2011-01-18
期刊：
影响因子：
50.3
通讯作者：
Ashkenazi, Avi
中科院分区：
文献类型：
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作者：
Wilson, Nicholas S.;Yang, Becky;Ashkenazi, Avi
细胞表面抗原的抗体触发白细胞中活化Fc γ受体（Fc γ R）介导的逆行信号，以控制免疫效应子功能。在这里，我们揭示了Fc γ R机制，驱动靶细胞中的抗体依赖性正向信号传导。死亡受体5（DR 5）的激动性抗体诱导癌细胞凋亡，并在临床试验中;然而，其在体内的作用机制尚未完全确定。DR 5激动性抗体drozitumab与白细胞Fc γ R的相互作用促进DR 5介导的肿瘤细胞凋亡。尽管抗CD 20抗体利妥昔单抗需要活化Fc γ R来实现杀肿瘤功能，但drozitumab在活化或抑制性Fc γ R的情况下均有效。CD 40激动性抗体需要类似的Fc γ R相互作用来刺激B细胞中的核因子-κ B活性。因此，Fc γ R可以驱动靶细胞中抗体介导的受体信号传导。
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.