一种新型树突状细胞疫苗靶向抑制肾癌干细胞的机制研究

项目名称： 一种新型树突状细胞疫苗靶向抑制肾癌干细胞的机制研究

项目编号： No.81472392

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： 田丰

作者单位： 中国人民解放军东部战区总医院

项目金额： 70万元

中文摘要： 肾癌干细胞（RCSC）是肾癌复发转移的关键，转化生长因子-β（TGF-β）在肿瘤细胞转移和对抗免疫治疗时具有重要作用。我们前期研究发现，阻断树突状细胞（DC）疫苗的TGF-β信号通路可以有效的抑制肾癌肺转移。但此种DC疫苗对RCSC是否具有相同的抑制作用，作用机制如何，尚不得而知。本课题根据前期研究基础，认为通过靶向性阻断TGF-β信号通路可以使DC细胞有效迁移至RCSC微环境，动员免疫细胞杀伤RCSC，抑制RCSC的增殖和转移。本研究拟通过分离肾癌患者的RCSC使SCID小鼠成瘤，再分离患者的DC及杀伤性T细胞（CTL），应用逆转录病毒来靶向性阻断DC细胞TGF-β信号通路，将此DC疫苗及CTL细胞回输小鼠，模拟人体内免疫系统，观察DC疫苗对RCSC体内体外的抑制作用情况，了解其可能机制。本研究是对既往研究的深入，更接近临床应用，有望为转移性肾癌个体化及免疫治疗提供新的思路和方法。

中文关键词： C12_肾；肾盂；输尿管肿瘤；晚期肾癌；肿瘤干细胞；树突状细胞；疫苗

英文摘要： Renal cancer stem cell(RCSC) is the key point of the recurrence and metastasis of kidney cancer. Transforming growth factor-β(TGF-β)is an important role in tumor metastasis and anti-immunotherapy. Our previous research showed blockade the pathway of TGF-β in dendritic cell(DC) could efficiently suppress the pulmonary metastasis of renal cancer. But whether this type of DC vaccine can also have the same effect on the RCSC and what the mechanism is are still not known. According to our previous researches, we presumed that targeting blocked the signal patheway of TGF-β, DC vaccines can efficiently migrate to the niche of RCSC and arouse the immune cell to destroy the RCSC, suppress the proliferation and metastasis of the tumor. In this research, we are planning to isolate the RCSC from patients with renal cancer and to implant these cells to SCID mice to form metastatic tumor. Then we isolate the DCs and CTLs from the same patient. By infected by retrovirus containing gene of pseudo-receptor of TGF-β, the DCs will be targetingly blocked the signal pathway of TGF-β and become TGF-βinsensitive. After transfusing this type of DCs and CTLs back to the tumor forming SCID mice, we can imitate the immune enviorment of human body to observe the situation of tumor growth. By series of observaion and test iv-vivo and in-vitro, eg. tumor weights, survival periods, cytokine levels, we can finally determin the effects of TGF-β insensitive DCs on RCSC and its niche, and find the possible mechanisms of it. Our research is the further investigation of the previous study. But it further close to clinical application and may provide a new thoughts and means to individualized treatment and immunotherapy of metastatic RCC patients.

英文关键词： renal cell carcinoma;advanced renal cancer;cancer stem cell;dendritic cell;vaccine