IL-6/STAT3/miR-155通路在早期髓系来源抑制细胞（e-MDSCs）分化障碍和乳腺癌内在亚型转换中的调控机制研究

早期髓系来源抑制细胞(e-MDSCs)是新发现的MDSCs亚群，具有独特的低分化表型和强免疫抑制活性。前期我们在乳腺癌中鉴别出一群具有类似表型和功能的e-MDSCs，既存在显著的髓系分化障碍，亦可促进乳腺癌内在亚型转换(ISS)。肿瘤源性IL-6可诱导e-MDSCs中JAK/STAT3通路持续激活，并上调髓系分化抑制分子miR-155水平，提示IL-6/STAT3/miR-155通路失调可能调控e-MDSCs的分化和促ISS活性。本研究拟从组织、细胞和动物三个层面探讨e-MDSCs分化障碍与乳腺癌ISS的相关性，围绕IL-6/STAT3/miR-155通路三个关键分子节点挖掘导致e-MDSCs分化障碍的主要分子事件，利用全转录组测序和条件敲除髓系SOCS3小鼠乳腺癌模型阐明其调控e-MDSCs生成和促乳腺癌ISS的机制，并观察干预上述通路在体内外对IL-6高表达乳腺癌生长和侵袭的抑制作用。

Early-stage MDSCs (e-MDSCs) are a newly identified subset of MDSCs, which possess unique immature phenotypes and potent immunosuppressive activity. In our previous study, we distinguished a subset of e-MDSCs with similar phenotype and function in breast cancer, which displayed significant differentiation block and promoted intrinsic subtype switching (ISS) of breast cancer. We found that tumor-derived IL-6 induced sustained activation of the JAK/STAT3 signaling pathway in e-MDSCs and upregulated the expression of miR-155, which implied that the IL-6/STAT3/miR-155 pathway might regulate the differentiation and activity of e-MDSCs. Therefore, in this study we shall systemically investigate the correlation between the distribution of e-MDSCs and the ISS of breast cancer, deeply probe the key molecular events inducing the differentiation block in e-MDSCs, and comprehensively elucidate the underlying mechanisms regulating the aberrantly activated IL-6/STAT3/miR-155 pathway in the generation and function of e-MDSCs using high-throughput genetic analysis and conditioned SOCS3 knockout transgenic murine mammary carcinoma models. Finally, we shall evaluate the anti-tumor effect of target therapy against above pathway in inhibiting tumor growth and metastasis of IL-6 high-expressing breast cancer both in vivo and vitro.