基于PPARα/PPRE合成基因线路调控多靶点抗原及GM-CSF表达的iPSC膀胱癌疫苗的构建及其靶向治疗膀胱癌的研究

开发有效的肿瘤疫苗是治疗恶性肿瘤的方法之一。肿瘤在发展过程中由于抗原丢失以及肿瘤细胞的免疫逃逸，导致靶向单一肿瘤抗原的疫苗极易失效。研究发现，iPSC与肿瘤细胞共同表达多种肿瘤抗原，作为预防性疫苗可有效减缓多种肿瘤生长，具有限制肿瘤细胞免疫逃逸的潜能。本课题将应用前期测序分析及验证得到的干细胞表达的肿瘤抗原以及膀胱癌细胞表达的新抗原，设计多靶点肿瘤抗原，结合筛选得到的免疫调节因子使其共同在iPSC内表达，构建新型的治疗性膀胱癌疫苗。为有效提高多靶点抗原以及免疫调节因子在iPSC内的表达效率，拟设计一条人工合成基因线路，利用安全的小分子药物激活PPARα信号通路和PPRE启动子调控目的基因的表达，通过靶向协同多种方式治疗膀胱癌。本课题的研究成果为开发和应用针对膀胱癌的治疗性干细胞疫苗提供理论和实验依据，为膀胱癌治疗提供新的策略。

The development of effective tumor vaccines is one of the methods to treat malignant tumors. Due to the loss of antigen and the immune escape of tumor cells during tumor development, vaccines that target a single tumor antigen are easily invalidated. iPSC and tumor cells co-express a variety of tumor antigens. As a preventive vaccine, it can effectively inhibit the growth of a variety of tumors and have the potential to limit the immune escape of tumor cells. In this project, we will use the tumor antigens co-expressed by iPSC and neoantigens expressed by bladder cancer cells to design multi-target tumor antigens, and combine the immune mediator to express them in iPSC to construct a new type of therapeutic bladder cancer vaccine. In order to improve the efficiency of iPSC, we designed an artificial synthetic gene circuit, used a small molecule drug to activate the PPARα signaling pathway and the PPRE promoter to regulate the expression of the target genes, though combine multi-way to treat cancer. The results of this subject will provide theoretical and experimental basis for the development and application of therapeutic stem cell vaccines against bladder cancer, and provide new strategies for the treatment of bladder cancer.