Visualization of immediate immune responses to pioneer metastatic cells in the lung

被引:325
作者
Headley, Mark B. [1 ]
Bins, Adriaan [1 ,2 ]
Nip, Alyssa [1 ]
Roberts, Edward W. [1 ]
Looney, Mark R. [3 ,4 ]
Gerard, Audrey [1 ]
Krummel, Matthew F. [1 ]
机构
[1] Univ Calif San Francisco, Dept Pathol, 513 Parnassus Ave,HSW512, San Francisco, CA 94143 USA
[2] Acad Med Ctr Amsterdam, Dept Med Oncol, Meibergdreef 9, NL-91105 AZ Amsterdam, Netherlands
[3] Univ Calif San Francisco, Dept Med, 513 Parnassus Ave,HSW512, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Dept Lab Med, 513 Parnassus Ave,HSW512, San Francisco, CA 94143 USA
关键词
T-CELL; REPORTER MOUSE; ANTIGEN; DIFFERENTIATION; EXPRESSION; MONOCYTES; EXOSOMES; GROWTH; MICE;
D O I
10.1038/nature16985
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Lung metastasis is the lethal determinant in many cancers(1,2) and a number of lines of evidence point to monocytes and macrophages having key roles in its development(3-5). 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(6) 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(3). 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 anti-metastatic 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.
引用
收藏
页码:513 / +
页数:14
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