Visualization of immediate immune responses to pioneer metastatic cells in the lung.
Visualization of immediate immune responses to pioneer metastatic cells in the lung.
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DOI：
10.1038/nature16985
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发表时间：
2016-03-24
期刊：
影响因子：
64.8
通讯作者：
Krummel MF
中科院分区：
文献类型：
--
作者：
Headley MB;Bins A;Nip A;Roberts EW;Looney MR;Gerard A;Krummel MF
肺转移是许多癌症中的致命决定因素，并且许多证据表明单核细胞和巨噬细胞在其发展中具有关键作用。然而，人们对进入的肿瘤细胞在这种组织中定居时的直接命运知之甚少，更不知道它们如何与免疫系统进行第一次接触。原发性肿瘤将循环肿瘤细胞（CTC）释放到血液中，我们已经在小鼠中开发了一种稳定的活体双光子肺成像模型，用于直接观察CTC的到达和随后的宿主相互作用。在这里，我们显示了CTC进入几分钟内毛细血管中剪切流中肿瘤微粒的动态生成。这些微粒中的许多不是在流动下分散，而是保持附着于肺脉管系统或独立地沿着血管内壁迁移。使用荧光谱系报告基因和流式细胞术，我们观察到不同的骨髓细胞亚群的“波”，这些细胞亚群不同地和顺序地负载这种CTC衍生的材料。许多这些肿瘤侵袭性髓样细胞与成功转移的细胞一起沿着聚集在肺结节中，并且如先前所理解的，促进从存活的肿瘤细胞成功转移的发展。尽管这些细胞的数量在肺中随着转移暴露而全面上升，并且骨髓细胞经历与微粒摄入相关的表型变化，但在最后与CTC相互作用的细胞中，常驻常规树突状细胞的一贯稀疏群体赋予抗转移保护。这项工作表明，CTC片段产生免疫相互作用的中间体，并定义了转移性细胞接种过程中肿瘤负荷的吞噬细胞群体之间的竞争关系。
Lung metastasis is the lethal determinant in many cancers and a number of lines of evidence point to monocytes and macrophages having key roles in its development. Yet little is known about the immediate fate of incoming tumour cells as they colonize this tissue and even less known about how they make first contact with the immune system. Primary tumours liberate circulating tumour cells (CTCs) into the blood and we have developed a stable intravital two-photon lung imaging model in mice for direct observation of the arrival of CTCs and subsequent host interaction. Here we show dynamic generation of tumour microparticles in shear flow in the capillaries within minutes of CTC entry. Rather than dispersing under flow, many of these microparticles remain attached to the lung vasculature or independently migrate along the inner walls of vessels. Using fluorescent lineage reporters and flow cytometry, we observed ‘waves’ of distinct myeloid cell subsets that load differentially and sequentially with this CTC-derived material. Many of these tumour-ingesting myeloid cells collectively accumulated in the lung interstitium along with the successful metastatic cells and, as previously understood, promote the development of successful metastases from surviving tumour cells. Although the numbers of these cells rise globally in the lung with metastatic exposure and ingesting myeloid cells undergo phenotypic changes associated with microparticle ingestion, a consistently sparse population of resident conventional dendritic cells, among the last cells to interact with CTCs, confer antimetastatic protection. This work reveals that CTC fragmentation generates immune-interacting intermediates, and defines a competitive relationship between phagocyte populations for tumour loading during metastatic cell seeding.