Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy
Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy
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DOI：
10.1038/s41586-021-03614-z
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发表时间：
2021-06-02
期刊：
影响因子：
64.8
通讯作者：
Bentires-Alj, Mohamed
中科院分区：
文献类型：
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作者：
Correia, Ana Luisa;Guimaraes, Joao C.;Bentires-Alj, Mohamed
原发性肿瘤切除术后不可检测的播散性肿瘤细胞（DTC）的持续存在对有效的癌症治疗构成了重大挑战（1-3）。这些持久的休眠DTC是未来转移的种子，需要定义将它们从休眠转变为生长的机制。由于癌症休眠为预防转移性疾病提供了一个独特的治疗窗口，因此必须全面了解休眠DTC储库的分布，组成和动态。在这里，我们发现不同的组织特异性微环境抑制或允许乳腺癌在肝脏中的进展-肝脏是一个常见的转移部位（4），通常与预后不良相关（5）。使用小鼠模型，我们表明，在休眠环境中，自然杀伤（NK）细胞有选择性增加。基于白细胞介素-15的辅助免疫疗法确保了大量NK细胞通过干扰素-γ信号传导维持休眠，从而预防肝转移并延长生存期。从休眠中退出后，NK细胞区室显著收缩，并同时积累活化的肝星状细胞（aHSC）。我们对肝脏共培养物的蛋白质组学研究表明，aHSC分泌的趋化因子CXCL 12通过其同源受体CXCR 4诱导NK细胞静止。CXCL 12表达和aHSC丰度在肝转移患者中密切相关。我们的数据将NK细胞和aHSC之间的相互作用确定为癌症休眠的主开关，并表明旨在使NK细胞库正常化的疗法可能成功地预防转移性生长。
The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment(1-3). These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver-a frequent site of metastasis(4) that is often associated with a poor prognosis(5). Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-gamma signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth.