小分子化合物诱导肺癌肿瘤干细胞形成及用其制备DC疫苗治疗肺癌的研究

肿瘤干细胞具有很强的抗化疗和抗放疗的特性，免疫细胞治疗被认为是清除肿瘤干细胞的有效途径，但如何获得肿瘤干细胞用于制备疫苗，是肿瘤干细胞靶向免疫治疗的瓶颈问题。近年来化学遗传学的快速发展，特别是发现几种小分子化合物的组合能够诱导体细胞重编程进而成功地获得iPS，为我们利用小分子化合物诱导肿瘤干细胞提供了理论基础和实践经验。申请人前期在Prostate上发表的研究结果表明通过过表达SOX2使前列腺肿瘤细胞LNCaP变成具有肿瘤干细胞的特性。我们在Stem Cells上发表的结果表明利用肿瘤干细胞反复冻融液作抗原负载DC疫苗，三次免疫后 在脑瘤动物模型体内产生肿瘤干细胞特异性的CTL并延长动物的生存期。本课题将采用小分子化合物的优化组合体外诱导肿瘤细胞重编程，获得诱导肿瘤干细胞（iCSC），重点研究iCSC的形成机制及免疫学特性并在EGFRL858R自发性肺癌动物模型上探讨iCSC疫苗的治疗效果

While many studies have demonstrated that tumor stem cells exhibit strong resistance to radiation and chemotherapy, immunotherapy has shown great promise as an effective approach to killing cancer stem cells. However, developing a method to quickly obtain enough tumor stem cells to prepare tumor vaccine is still a key bottom neck challenge in the pursuit of targeted cancer immunotherapy. Recently, the development of Chemical Genetics has led to the discovery that inducing somatic cell reprogramming can successfully generate induced pluripotent stem cells (iPS). This finding provided the theoretical basis and practical experience to explore inducible cancer stem cells (iCSC) using small-molecule compounds. Our study in Prostate demonstrated that LNCaP prostate cancer cells can become cancer stem-like cells by over-expressing SOX2, while our study in Stem Cells found that proteins derived via repeated freezing and thawing from cancer stem cells can be used as the antigen to prepare dendritic cell (DC) vaccine. Three time vaccinations, which contained vaccine with tumor associated antigen derived from cancer stem cells could produce specific CTL, significantly improved the survival rate in brain tumor animal model. In this study, we seek to optimize the combination of small-molecule compounds in vitro to induce tumor cell reprogramming and to produce a significant number of iCSC. Then we will explore the mechanism by which iCSC form and study their immunological characteristics, as well as the efficacy of iCSC DC cancer vaccine in a novel EGFRL858R transgenic spontaneous lung cancer mouse model.