Macrophages eliminate circulating tumor cells after monoclonal antibody therapy
Macrophages eliminate circulating tumor cells after monoclonal antibody therapy
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DOI：
10.1172/jci66776
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发表时间：
2014-02-01
影响因子：
15.9
通讯作者：
van Egmond, Marjolein
中科院分区：
文献类型：
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作者：
Gul, Nuray;Babes, Liane;van Egmond, Marjolein
在过去的十年中，使用单抗作为治疗工具的数量急剧增加，现已成为治疗癌症的主流策略之一。尽管如此，单抗如何介导肿瘤细胞清除或参与其中的效应细胞仍不完全清楚。在活体显微镜下，我们发现，在小鼠肿瘤细胞调理模型中，巨噬细胞的抗体依赖吞噬作用(ADPH)是将肿瘤细胞从循环中移除的一个重要机制。肿瘤细胞被肝巨噬细胞(Kupffer细胞)迅速识别和阻断。在没有单抗的情况下，Kupffer细胞对肿瘤细胞进行采样；然而，这种采样不足以消除。相反，抗肿瘤单抗治疗可导致Kupffer细胞对肿瘤细胞的快速吞噬，这种吞噬作用依赖于高亲和力免疫球蛋白结合的Fc受体(Fc Gamma RI)和低亲和力的Ig G结合的Fc受体(Fc Gamma RIV)。摄取和细胞内降解与活性氧或氮物种的产生无关。重要的是，ADPH阻止了肝转移的发展。Kupffer细胞耗尽后，肿瘤细胞捕获和治疗效果丧失。我们的数据表明，巨噬细胞在单抗介导的肿瘤细胞根除过程中发挥着重要作用。这些发现可能有助于通过帮助我们提高巨噬细胞的募集和活性来优化癌症患者的单抗治疗策略。
The use of monoclonal antibodies (mAbs) as therapeutic tools has increased dramatically in the last decade and is now one of the mainstream strategies to treat cancer. Nonetheless, it is still not completely understood how mAbs mediate tumor cell elimination or the effector cells that are involved. Using intravital microscopy, we found that antibody-dependent phagocytosis (ADPh) by macrophages is a prominent mechanism for removal of tumor cells from the circulation in a murine tumor cell opsonization model. Tumor cells were rapidly recognized and arrested by liver macrophages (Kupffer cells). In the absence of mAbs, Kupffer cells sampled tumor cells; however, this sampling was not sufficient for elimination. By contrast, antitumor mAb treatment resulted in rapid phagocytosis of tumor cells by Kupffer cells that was dependent on the high-affinity IgG-binding Fc receptor (Fc gamma RI) and the low-affinity IgG-binding Fc receptor (Fc gamma RIV). Uptake and intracellular degradation were independent of reactive oxygen or nitrogen species production. Importantly, ADPh prevented the development of liver metastases. Tumor cell capture and therapeutic efficacy were lost after Kupffer cell depletion. Our data indicate that macrophages play a prominent role in mAb-mediated eradication of tumor cells. These findings may help to optimize mAb therapeutic strategies for patients with cancer by helping us to aim to enhance macrophage recruitment and activity.