FAPα阳性骨髓基质细胞抑制抗多发性骨髓瘤免疫反应及其机制研究

项目名称： FAPα阳性骨髓基质细胞抑制抗多发性骨髓瘤免疫反应及其机制研究

项目编号： No.81471532

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 何静松

作者单位： 浙江大学

项目金额： 90万元

中文摘要： 多发性骨髓瘤（MM）是一种单克隆浆细胞异常增生的血液系统恶性肿瘤，患者抗MM免疫功能状态对疗效和生存至关重要。近年在肺癌和胰腺癌小鼠模型中发现一类成纤维细胞激活蛋白α（FAPα）阳性的肿瘤基质细胞是抑制抗肿瘤免疫的关键因素。我们前期研究发现，在MM患者骨髓FAPα+细胞的比例与其临床疗效相关，体外培养的骨髓基质细胞（BMSCs）在FAPα的介导下，保护MM细胞抵抗硼替佐米诱导的细胞凋亡，并分泌高水平TGF-β等免疫抑制因子，提示FAPα+ BMSCs可能参与抑制抗MM免疫应答，但FAPα是否在其中起到关键作用？其作用的具体机制是什么？尚不清楚。故本课题拟以FAPα+ BMSCs为主要研究对象，在体外细胞培养体系和MM动物模型中，采用免疫学和分子生物学研究方法，深入探讨FAPα在BMSCs抑制抗MM特异性免疫反应中的重要作用，寻找MM免疫逃逸的关键点，为进一步设计靶向免疫治疗提供实验依据。

中文关键词： C17_骨髓瘤；基质细胞；FAPα；肿瘤免疫；T细胞

英文摘要： Multiple myeloma (MM) is a malignant neoplasm of abnormal monoclonal plasma cell proliferation. Anti-tumor immunity of patients plays an important role in efficacy and survival of MM. It was reported that fibroblast activation protein α (FAPα) positive tumor stromal cells were key factors of anti-tumor immunity inhibition in lung cancer and pancreatic cancer in mouse models . Our also found that the proportion of FAPα positive cells in bone marrow of patients with MM was related to patients' efficacy, bone marrow stromal cells (BMSCs) in vitro could protect MM cells from bortezomib-induced apoptosis mediated by FAPα, and secret high levels of TGF-β and other immunosuppressive factors, suggesting a critical role of FAPα positive BMSCs in the inhibition of anti-tumor immunity. But the role of FAPα and the specific mechanism remains unknown. Here, we study the important role of FAPα in inhibition of anti-myeloma immunity by BMSCs to find the key points of immune evasion in MM by immunology and molecular biology research methods in vitro cell culture systems and animal models, to provide experimental evidence for further design targeted immunotherapy.

英文关键词： multiple myeloma;stromal cell;FAPα;tumor immunity;T lymphocyte