Breast cancer patients with estrogen receptor positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cancer cells display “stem like” properties (CSCs), which may be regulated by the immune system. To elucidate the role of the immune system in controlling dormancy and its escape, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. Three mouse breast cancer cell lines, PyMT, Met-1 and D2.0R, contained CSCs that displayed both short- and long-term metastatic dormancy in vivo, which was dependent on the host immune system. Each model was regulated by different components of the immune system. Natural killer (NK) cells were key for the metastatic dormancy phenotype in D2.0R cells. Quiescent D2.0R CSCs were resistant to NK cell cytotoxicity, while proliferative CSCs were sensitive. Resistance to NK cell cytotoxicity was mediated, in part, by expression of BACH1 and SOX2 transcription factors. Expression of STING and STING targets was decreased in quiescent CSCs, and the STING agonist MSA-2 enhanced NK cell killing. Collectively, these findings demonstrate the role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon.

中文翻译：

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乳腺癌干细胞的自然杀伤细胞调节介导转移性休眠


患有雌激素受体阳性肿瘤的乳腺癌患者在其余生中一直面临疾病复发的风险。驻留在骨髓等组织中的休眠肿瘤细胞可能在初步诊断多年后产生具有临床意义的转移。先前的研究表明，休眠的癌细胞表现出“干细胞样”特性 （CSC），这可能受到免疫系统的调节。为了阐明免疫系统在控制休眠及其逃逸中的作用，我们研究了免疫功能正常的同基因小鼠乳腺癌模型中的休眠。三种小鼠乳腺癌细胞系 PyMT 、 Met-1 和 D2.0R 含有 CSCs，它们在体内表现出短期和长期转移休眠，这取决于宿主免疫系统。每个模型都受免疫系统的不同组成部分的调节。自然杀伤 （NK） 细胞是 D2.0R 细胞转移休眠表型的关键。静止的 D2.0R CSCs 对 NK 细胞毒性具有抵抗力，而增殖性 CSCs 对 NK 细胞毒性敏感。对 NK 细胞细胞毒性的耐药部分是由 BACH1 和 SOX2 转录因子的表达介导的。在静止的 CSCs 中，STING 和 STING 靶标的表达降低，STING 激动剂 MSA-2 增强了 NK 细胞杀伤。总的来说，这些发现证明了免疫调节对乳腺肿瘤休眠的作用，并强调了利用免疫活性模型研究这一现象的重要性。