小柯机器人

瑞士巴塞尔大学Mohamed Bentires-Alj、Ana Luísa Correia等研究人员合作发现，肝星状细胞抑制NK细胞维持的乳腺癌休眠。这一研究成果于2021年6月2日在线发表在国际学术期刊《自然》上。

研究人员表明，不同的组织特异性微环境会抑制或允许乳腺癌在肝脏中的进展——肝脏是常见的转移部位，通常与不良预后相关。使用小鼠模型，研究人员表明休眠环境中自然杀伤（NK）细胞有选择性地增加。基于白细胞介素15的辅助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，从而预防肝转移并延长生存期。在NK细胞区室显著的减少以及激活型肝星状细胞（aHSC）的同时积累之后，肿瘤细胞会退出休眠状态。

研究人员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。这些数据将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会成功预防转移性生长。

据了解，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提出了重大挑战。这些持久的休眠DTC是未来转移的种子，将它们从休眠状态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库的分布、组成和动态。

附：英文原文

Title: Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy

Author: Ana Lusa Correia, Joao C. Guimaraes, Priska Auf der Maur, Duvini De Silva, Marcel P. Trefny, Ryoko Okamoto, Sandro Bruno, Alexander Schmidt, Kirsten Mertz, Katrin Volkmann, Luigi Terracciano, Alfred Zippelius, Marcus Vetter, Christian Kurzeder, Walter Paul Weber, Mohamed Bentires-Alj

Issue&Volume: 2021-06-02

Abstract: The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment1,2,3. 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.

DOI: 10.1038/s41586-021-03614-z

Source: https://www.nature.com/articles/s41586-021-03614-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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