Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy,Nature

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Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy
Nature ( IF 50.5 ) Pub Date : 2021-06-02 , DOI: 10.1038/s41586-021-03614-z
Ana Luísa Correia _{1,

2,

3} , Joao C Guimaraes _{4,

5} , Priska Auf der Maur _{1,

3} , Duvini De Silva _{1,

2,

5} , Marcel P Trefny ₁ , Ryoko Okamoto _{1,

2,

3,

6} , Sandro Bruno _{2,

7} , Alexander Schmidt ₈ , Kirsten Mertz ₉ , Katrin Volkmann _{1,

3} , Luigi Terracciano ₁₀ , Alfred Zippelius _{1,

11} , Marcus Vetter _{11,

12,

13} , Christian Kurzeder _{12,

13} , Walter Paul Weber _{3,

13} , Mohamed Bentires-Alj _{1,

2,

3}

Affiliation

Department of Biomedicine, University of Basel, Basel, Switzerland.
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Department of Surgery, University Hospital Basel, Basel, Switzerland.
Computational and Systems Biology, Biozentrum, University of Basel, Basel, Switzerland.
F. Hoffmann-La Roche AG, Basel, Switzerland.
Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland.
Institute of Pathology Liestal, Cantonal Hospital Basel-Land, Liestal, Switzerland.
Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Department of Medical Oncology, University Hospital Basel, Basel, Switzerland.
Gynecologic Cancer Center, University Hospital Basel, Basel, Switzerland.
Breast Center, University of Basel and University Hospital Basel, Basel, Switzerland.

The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment^1,2,3. 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 metastasis⁴ that is often associated with a poor prognosis⁵. 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-γ 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.

中文翻译：

肝星状细胞抑制 NK 细胞维持的乳腺癌休眠

原发性肿瘤切除后无法检测到的播散性肿瘤细胞 (DTC) 的持续存在对有效的癌症治疗^1,2,3构成了重大挑战。这些持久的休眠 DTC 是未来转移的种子，将它们从休眠转变为生长的机制需要定义。由于癌症休眠为预防转移性疾病提供了独特的治疗窗口，因此必须全面了解休眠 DTC 储库的分布、组成和动态。在这里，我们展示了不同的组织特异性微环境抑制或允许肝癌在肝脏中的进展——这是一个常见的转移部位⁴，通常与预后不良有关⁵. 使用小鼠模型，我们显示休眠环境中自然杀伤 (NK) 细胞的选择性增加。辅助的基于白细胞介素 15 的免疫疗法可确保大量 NK 细胞通过干扰素-γ 信号传导维持休眠，从而防止肝转移并延长生存期。在 NK 细胞室显着收缩和活化的肝星状细胞 (aHSC) 的同时积累之后，退出休眠。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 CXCL12 通过其同源受体 CXCR4 诱导 NK 细胞静止。CXCL12 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，

更新日期：2021-06-02

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