肿瘤相关巨噬细胞(TAMs)是肿瘤微环境数目最多的炎症间质细胞，调节性T淋巴细胞（Tregs）是导致肿瘤免疫抑制的主要执行细胞。最近报道Tregs与赫赛汀耐药密切相关，但TAMs是否通过招募或激活Tregs诱导赫赛汀耐药及潜在机制尚不清楚。我们前期研究发现CCL18是人乳腺癌标本中TAMs分泌最多的细胞因子，CCL18表达和病人不良预后相关。我们预实验显示CCL18能募集Tregs到乳腺癌，Tregs通过诱导CD8+杀伤性T淋巴细胞凋亡导致肿瘤免疫抑制，并通过未知机制诱导乳腺癌赫赛汀耐药。在此基础上，本课题拟通过病人组织分析、体外和体内实验模型进一步阐明肿瘤微环境中炎症间质细胞相互作用机制，研究Tregs对乳腺癌赫赛汀耐药的作用，以及探索针对CCL18受体发展新型靶向药物的治疗策略。本研究将有助于揭示肿瘤微环境调控乳腺癌生物学特性的分子机制，并为发展逆转常规治疗耐药的新靶向治疗提供理论基础

The tumor microenvironment comprises a variety of inflammatory stromal cells. Among them, tumor associated macrophages (TAMs) are the most common cells, while T regulatory cells (Tregs) are the main cells responsible of tumor immunosuppresion. Evidence from recent studies has shown a strong association between Tregs and herceptin-resistance. From our previous studies, we found that breast TAMs abundantly produce CCL18, and its expression is associated with metastasis and reduced patient survival. Moreover, our results showed that CCL18 can recruit Tregs to breast tumor stroma and Tregs can induce the apotosis of CD8+ cytotoxic T lymphocytes which results in tumor immunosuppression and herceptin-resistance in breast cancer via unknown mechanism. On this basis, this study will clarify the interaction between inflammatory stromal cells in tumor microenviroment via analysis of patients tissue spicemens, experimental model in vitro and in vivo and the role of Tregs in herceptin-resistance of breast cancer. Furthermore, this study will be benefit for revealing the molecular mechanism of inflammatory microenviroment regulating breast cancer characteristic, and provide the therory basis of new targeted drug.