新型疫苗FAPt-MT抗肿瘤效应的机制研究

As a promising tumor immunotherapy strategy, polypeptide vaccine has attracted more and more attention. However, the tumor vaccines always appear the worse clinical results in practical application. To investigate its reason, there are existing two factors. On the one hand is the reason of tumor itself. Targeted tumor antigens variation and lost resulted from genomic instability led to tumor immune escape. Therefore, the choice for tumor vaccine is turning from antigens of tumor cell to antigens of tumor stromal cell. Fibroblast activation protein α (FAPα) derived from tumor associated fibroblasts is frequently explored as a candidate target for tumor therapy. On the other hand is the host reason. Inhibitory molecules generated in the host resulted in its low antitumor function. Indolamine2,3-dioxygenase (IDO) is supposed to play important roles in mediating tumor immune tolerance. As above, we constructed the new tumor vaccine FAPt-MT and confirmed its anti-tumor activity in our previous study. In this study, we will further explore anti-tumor mechanisms of the new tumor vaccine and how FAPt-MT regulate the tumor immune microenvironment. This study will provide the first hand information for its application and dissemination.

作为一种有前景的肿瘤免疫治疗策略，肿瘤多肽疫苗的研究备受重视。然而其实际临床效果却往往不尽人意。究其原因，两个方面的因素不可忽视。一方面是肿瘤自身的因素，即肿瘤细胞基因的不稳定性导致靶抗原变异和丢失引起肿瘤免疫逃逸。因此，肿瘤疫苗的选择从传统的肿瘤细胞表面抗原逐渐转向肿瘤间质细胞表面抗原。表达于肿瘤间质成纤维细胞表面蛋白-成纤维细胞激活蛋白a（FAPa），作为一种极具潜力的抗肿瘤靶标分子正备受关注。另一方面是宿主的因素，荷瘤宿主内抑制性分子的产生，导致机体抗肿瘤功能低下。吲哚胺2，3双加氧酶（IDO）被认为是介导肿瘤免疫耐受的关键环节。因此，我们在前期研究中将IDO特异性抑制剂1-MT修饰至FAPa,构建了嵌合蛋白FAPt-MT，并证实该疫苗具有良好抗肿瘤作用。本课题我们将进一步探讨FAPt-MT对肿瘤微环境的免疫调节作用，阐明其抗肿瘤机制。本研究将为实现该疫苗的推广应用提供有力依据。

鉴于新型肿瘤疫苗FAPt-MT针对的靶点为FAPa，本项目以FAPa为研究对象，探讨FAPa在肿瘤免疫微环境和肿瘤发生发展过程中的作用及调控机制。一方面在患者肿瘤组织内检测了FAPa表达，探讨了肿瘤组织内FAPa表达与肿瘤浸润淋巴细胞及患者预后的相关性；另一方面在肿瘤细胞内鉴定FAPa表达前后对细胞功能的影响并明确FAPa表达的调控机制。FAPa在胃癌肿瘤细胞和肿瘤间质中大量表达，并与患者预后呈负相关。FAPa与CD4+、CD8+ T淋巴细胞浸润均不具有相关性。FAPa与胃癌肿瘤组织中TGFb表达呈正相关。在胃癌细胞MGC-803中，TGFb通过经典smad通路和非经典p38-MAPK通路联合上调FAPa表达。在恶性黑色素瘤细胞B16中，EMT相关转录因子Snail、Twist通过与FAPa启动子区E-box结合，直接调控FAPa表达。FAPa表达能促进肿瘤细胞的浸润转移。这些研究结果为以FAPa为靶点的抗肿瘤治疗策略提供了新的方向，为新型疫苗FAPt-MT的抗肿瘤机制提供了有力证据。