特异溶瘤腺病毒干预NKG2D信号治疗前列腺癌的实验研究

项目名称： 特异溶瘤腺病毒干预NKG2D信号治疗前列腺癌的实验研究

项目编号： No.81472396

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： 胡泽斌

作者单位： 中国人民解放军军事科学院军事医学研究院

项目金额： 72万元

中文摘要： 转移或激素非依赖型前列腺癌目前仍然缺乏有效治疗手段。免疫治疗可能是该类肿瘤晚期的最佳选择之一。NK细胞作为天然免疫的重要效应细胞和CD4+细胞非依赖性CTLs诱导的中心环节，是肿瘤免疫治疗的重要靶标。前列腺癌患者肿瘤细胞高表达的ADAM10/17可导致可溶性NKG2DL产生，而分泌的TGF-β则可下调NK细胞NKG2D受体，进而影响NKG2D信号和NK细胞的激活。本研究拟采用前列腺癌特异溶瘤腺病毒为载体，采用双shRNA干涉肿瘤细胞ADAM10/17和TGF-β的表达，研究其体外特异性溶瘤功能，NK细胞、DC、T淋巴细胞的免疫激活作用及机制；建立完全免疫系统和NK细胞功能缺失的荷瘤小鼠模型，评价体内溶瘤、免疫激活、抗肿瘤效应及机制，明确NK细胞在NKG2DL介导抗肿瘤免疫中的作用；探讨ADAM10/17干涉和TGF-β干涉的协同效应及机制。预期为前列腺癌免疫基因治疗提供新的、更有效的策略。

中文关键词： 前列腺癌；溶瘤腺病毒；NKG2D；ADAM；转化生长因子β

英文摘要： Currently there is a lack of effective treatments for metastasized or hormone resistant prostate cancer. Immune therapy may be one of best choices for treatment of these diseases. As an important target of tumor immune therapy, natural killer (NK) cells can not only exert direct cytotoxic functions, but also induce CD4+ helper cell-independent CTL responses. High expression of a disintegrin and metalloproteinase (ADAM) 10/17 on prostate cancer cells mediated the production of souble Natural killer group 2 D (NKG2D) ligand. Prostate cancer cells can also secret transforming growth factor-β(TGF-β), which could downregulate the NKG2DL expression on NK cells. The downregulation of NKG2DL and NKG2D can infulence NK activation by intervention of NKG2D-NKG2DL singal. In this study, we will inhibit ADAM10/17 and TGF-β expression simultaneously by using oncolytic adenovirus carrying dual specific shRNA. The specific oncolytic ability and mechanism of immune activation of NK cells, dendritic cells and T lymphocytes will be evaluated in vitro. Mouse-derived prostate cancer cells were implanted to normal or NK defective C57 mice to establish prostate cancer burdened mice model. Furthermore,oncolytic adenovirus will be injected into tumor to evaluate the therapeutic effect and immune response including activation of NK cells, T lymphocytes and DC. The synergistic effect for interference of ADAM10/17 and TGF-β will also be discussed. The results will provide a novel therapeutic strategy to treat prostate cancer more efficiently.

英文关键词： Prostate Cancer;Oncolytical adenovirus;NKG2D;ADAM;TGF-β