硝基化CD4+T细胞表位诱导表位扩展的机制研究及其在靶向KRAS突变的肿瘤新生抗原疫苗设计中的应用

KRAS突变是驱动肿瘤发生的重要因素，近90%的胰腺癌患者都携带此突变。近期研究发现，KRAS突变在某些患者体内可以作为肿瘤新生抗原激活免疫系统，提示其可以作为肿瘤免疫治疗靶点。但由于肿瘤形成经历了免疫选择压力，KRAS突变在大多数患者体内都是不能激活免疫应答的弱势表位。我们构建了一种硝基化CD4+T细胞表位，能通过表位扩展作用触发机体对原本不能诱导免疫应答的弱势表位产生强效应答并形成免疫记忆。同时，该表位可突破MHC多态性限制，在不同遗传背景的患者体内发挥作用。本项目拟借助这种硝基化CD4+T细胞表位设计靶向KRAS突变的肿瘤疫苗。通过对硝基化CD4+T细胞表位诱导表位扩展的机理进行深入研究，建立利用该表位设计肿瘤新生抗原疫苗的通用策略，设计并筛选出一系列靶向KRAS热点突变的疫苗候选分子，在不同遗传背景的患者体内激活针对KRAS突变的免疫应答，为携带KRAS突变的患者提供新的治疗策略。

KRAS mutations are one of the most important factors in driving tumorigenesis, and nearly 90% of patients with pancreatic cancer carry KRAS mutation. Recent studies have found that KRAS mutations can activate the immune system in some patients, suggesting that it may be an ideal target for tumor immunotherapy. However, because tumor formation has undergone immune stress selection, KRAS mutations are weak epitopes that do not activate the immune response in most patients. We had constructed a nitrated CD4+ T cell epitope that can trigger a potent response against a weak epitope that would not induce immune response, and form an immune memory. At the same time, this epitope can break through the MHC polymorphism and play a role in patients with different genetic backgrounds. This project intends to design a tumor vaccine targeting KRAS mutations by means of this nitroated CD4+ T cell epitope. Through in-depth study of the mechanism of epitope spreading induced by nitroated CD4+ T cell epitopes, we will establish a general strategy for designing tumor neoantigen vaccines using this epitope, and design and screen a series of vaccines targeting KRAS hotspot mutations to activate immune responses against KRAS mutations in patients with different genetic backgrounds, providing new therapeutic strategies for tumors carrying KRAS mutations.