Both activating and inhibitory Fc gamma receptors mediate rituximab-induced trogocytosis of CD20 in mice
- 作者：Peter Boross ; J.H. Marco Jansen ; Agnieszka Pastula ; Cees E. van der Poel ; Jeanette H.W. Leusen ; jleusen@umcutrecht.nl
- 关键词：Fc receptor ; CD20 ; Rituximab ; Trogocytosis
- 刊名：Immunology Letters
- 出版年：2012
- 期刊代码：115_01652478
- 类别：med
- 出版时间：30 March, 2012
- 卷：143
- 期：1
- 页码：44-52
- 文件大小：1009 K
摘要
Antigenic modulation by trogocytosis during anti-CD20 mAb treatment with rituximab (RTX) leads to loss of CD20 and therefore can compromise therapy. During trogocytosis, effector cells, such as macrophages, remove CD20 from the surface of antibody-coated cells in an Fc receptor-dependent manner. Importantly, Fc纬 receptors (Fc纬Rs) are also crucial in the anti-tumor effects of RTX by inducing antibody dependent cell-mediated cytotoxicity (ADCC). Here we studied the role of Fc纬R during RTX-induced trogocytosis of CD20 in an intraperitoneal tumor model with EL4-CD20 cells. We found marked RTX-induced trogocytosis of CD20 in Fc纬RI- or Fc纬RIII-deficient mice, similar to wild type mice, demonstrating a redundancy for activating Fc纬R in trogocytosis. Interestingly, in FcR纬-chain-deficient mice, trogocytosis was still apparent, indicating that the inhibitory receptor Fc纬RIIB alone can also mediate trogocytosis. These data were confirmed by in vitro analysis with blocking antibodies. Decreasing the amount of RTX in vivo resulted in less trogocytosis of CD20, supporting clinical studies with lower RTX dose. Importantly, we show that cells which undergo in vivo trogocytosis can still be killed ex vivo by ADCC but not by complement-mediated cytotoxicity (CDC), underscoring the clinical relevance of trogocytosis.
Taken together, our study provides more insights into the mechanism and consequences of RTX-induced trogocytosis of CD20.