肿瘤干细胞moesin通过CREB信号通路抑制三阴性乳腺癌CD8+T细胞功能的机制研究

三阴性乳腺癌是一种具有高复发率、高转移率的乳腺癌亚型，常规分子靶向治疗难以奏效。丰富的淋巴细胞浸润是其重要的病理学特征，但相关免疫检查点阻断疗法效果目前尚不理想，深入阐明该肿瘤免疫抑制调控机制非常重要。我们初步实验发现moesin上调乳腺癌干细胞比例进而促进三阴性乳腺癌恶性进展，且肿瘤细胞中moesin表达和CD8+T细胞功能抑制相关，其可活化下游CREB信号通路上调TGFβ等免疫抑制分子的分泌。因此我们提出“肿瘤干细胞中moesin通过活化下游CREB信号通路上调关键免疫抑制分子的表达，介导三阴性乳腺癌中CD8+T细胞功能抑制”的科学假设。基于此，我们拟从临床样本分析、体外功能实验、动物成瘤实验、分子机制研究和组学分析以及动物治疗实验等方面开展研究，以期阐明moesin及下游关键分子介导三阴性乳腺癌中CD8+T细胞功能抑制的作用及机制，为三阴性乳腺癌免疫治疗提供新的治疗靶点和实验依据。

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high recurrence rate and high metastasis rate, in which conventional molecular targeted therapy is difficult to achieve curative effect. Abundant lymphocyte infiltration is an important pathological feature of TNBC, but the effect of related immune checkpoint blocking therapy is not ideal at present. It is very important to further clarify the regulatory mechanism of immunosuppression in TNBC. Our preliminary results showed that moesin up-regulated the proportion of breast cancer stem cells and promoted the malignant progression of TNBC. The expression of moesin in tumor cells was related to the inhibition of CD8 positive T cell function. Moesin could activate downstream CREB signaling pathway and up-regulate the secretion of TGF β and other immunosuppressive molecules. Therefore, we propose the scientific hypothesis that moesin in cancer stem cells up-regulates the expression of key immunosuppressive molecules through activating downstream CREB signaling pathway, and mediates the functional inhibition of CD8 positive T cells in TNBC. Based on this, we plan to carry out research from the aspects of clinical sample analysis, function experiments in vitro, animal tumorigenesis experiment in vivo, molecular mechanism research and omics analysis, and animal treatment experiment, in order to clarify the role and molecular mechanism of moesin and downstream key molecules in the inhibition of CD8 positive T cell function in TNBC, and provide new therapeutic targets and experimental basis for immunotherapy of TNBC.