基于间充质干细胞的肿瘤免疫反应调控机制和对抗新策略

项目名称： 基于间充质干细胞的肿瘤免疫反应调控机制和对抗新策略

项目编号： No.81330046

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 时玉舫

作者单位： 中国科学院上海生命科学研究院

项目金额： 290万元

中文摘要： 癌症的发生、转移和对放化疗抵抗是导致患者死亡的主要原因。它的形成、进展和转归不只涉及肿瘤细胞自身的恶性增殖和转移，其与肿瘤免疫反应状态密切相关。我们的研究发现，间充质干细胞（MSC）与免疫的交互作用促进肿瘤免疫耐受状态的形成，调控肿瘤生长。此外，抑癌基因突变的MSC也通过调控免疫反应影响肿瘤生长。究竟肿瘤免疫抑制状态的塑造如何受MSC的调控仍尚不清楚。因此，我们提出假设内因、外因调控的MSC在塑造肿瘤免疫耐受和调控肿瘤病理进程中发挥重要作用。围绕这一假设，本项目拟探讨1）炎症性细胞因子塑造MSC调控肿瘤免疫特性的多样性；2）抑癌基因缺陷的MSC调控肿瘤免疫耐受的作用和机制；3）放疗或化疗处理的MSC对肿瘤免疫反应的调节作用和机制；4）探索以MSC为靶点的肿瘤治疗新策略。我们的研究以MSC为视角，多层次分析肿瘤发生、发展和转归的免疫逃逸机制，提出肿瘤病理机制的新概念，形成治疗肿瘤的新策略。

中文关键词： C20_皮肤及黑色素瘤;间充质干细胞;肿瘤免疫耐受;炎症性细胞因子;肿瘤治疗

英文摘要： Cancer is a leading cause of death. Tumor progression is associated with cancer cell immortality, metastases, and resistance to chemotherapy and radiotherapy. In addition to the uncontrolled tumor cell growth, emerging evidence reveals that immune responses play important roles in the progression of incipient neoplasia, late-stage tumors, and metastases. Our recent study found that the orchestration of mesenchymal stem cells (MSCs), immune cells, and inflammatory factors resulted in a tumor immunosuppressive environment, whereby facilitating tumor growth. Moreover, our preliminary data also revealed that dysregulation of p53 expression in MSCs (not in tumor cells) can promote tumor growth through downregulating T cell activation. These studies, therefore, shed new light on the pivotal role of MSCs in the formation of tumor immunosuppressive status, however, the detailed mechanisms are not clear. Here we hypothesize that MSCs can specifically migrate into tumor and become immunosuppressive and tumor promoting under the influence of the inflammatory microenvironment. We propose 4 specific aims to test this hypothesis. Based on the crosstalk between MSCs and immune responses, we will determine 1) the mechanisms of inflammatory cytokines in modulating the immunoregulatory properties of MSCs in tumor sites; 2) the role of tumor suppressor gene in MSCs in modulating the immune response status in tumor sites; 3) the effects of chemotherapeutic reagents or radiation treated MSCs on the formation of immunosuppressive tumor microenvironment; 4) the potential MSC-based tumor therapy. We believe that the completion of this study will provide not only the critical information for understanding of the formation of tumor cell evading immunosuppressive microenvironment, but also for designing new anti-cancer strategies.

英文关键词： melanoma;mesenchymal stem cells;tumor immune tolerance;inflammatory cytokine;tumor therapy