克服免疫抑制肿瘤微环境的“鸡尾酒siRNAs”/CpG ODNs/自组装多肽纳米共递送原位疫苗的设计、构建及评价

近年来肿瘤免疫治疗取得了巨大的进展。如何有效地释放肿瘤突变新抗原，克服抑制性肿瘤微环境TME诱导有效的免疫反应是提高肿瘤免疫治疗效果必须解决的关键问题。前期研究表明：自主设计的自组装多肽纳米粒子具有小核酸递送载体和佐剂的双重功能，可用于原位纳米疫苗的设计。已搭建针对抑制性TME复杂网络的多重因素的siRNA设计及筛选平台，该原位纳米疫苗将诱导肿瘤细胞凋亡、克服多重抑制性的TME和佐剂功能有机地结合在一起，增强抗肿瘤免疫活性。本课题将进一步探讨这种鸡尾酒siRNAs/CpG/自组装多肽纳米共递送原位疫苗在不同冷热肿瘤模型中的抗肿瘤效果，与免疫检查点抑制剂联用的协同作用机制，探讨冷热肿瘤TME转换的影响因素及多重靶点的协同作用分子机制，开发一种新型的克服抑制性TME、针对多种肿瘤的原位纳米疫苗，同时也为优化以此为基础的肿瘤原位疫苗及TME中不同靶点的联用设计及协同作用提供坚实的理论基础。

In recent years, cancer immunotherapy had achieved great progress. The key problems which could improve the efficacy of cancer immunotherapy, still focus on how to effectively release the tumor specific neoantigens and overcome immunosuppressive tumor microenvironment (TME). It was found in our previous study that a novel type of hydrophobically modified cationic peptide DP7-C, by adding cholesterol to a formerly identified highly active AMP (DP7), could self-assemble into stable nanomicelles in aqueous solution. The dual functions of DP7-C, as a small nucleic acids carrier and an immune adjuvant, make it a perfect nanocarrier for in situ vaccination in cancer immunotherapy. We had established a design and screening evaluation system of multiple factors of the complex network of immunosuppressive TME. The in situ nanovaccine could combine the induction of tumor cell apoptosis, the inhibition of the immunosuppressive TME and the use of adjuvant to enhance antitumor immune responses. The main research topic of our project is further exploring the antitumor effect of this “cocktail siRNAs”/ CpG ODNs /self-assembled peptide DP7-C in situ nanovaccine in different “cold” and “hot” tumor mouse models, discussing the synergistic effects combined with immune checkpoint inhibitor (anti-PD-1 mAb), studying the important TME-related factors of the conversion of “cold” to “hot” tumor, exploring the molecular mechanism of the synergy of different targets and providing a novel in situ nanovaccine that overcomes the immunosuppressive TME in multiple tumors.