长期以来，阻断肿瘤免疫逃逸一直是肿瘤疫苗设计中的一个挑战。由于肿瘤细胞能通过免疫耐受和免疫抑制等多种途径获得免疫逃逸能力，单一靶点的疫苗设计难以有效阻断其逃逸。免疫原性氨基酸是一类能使自体蛋白突破免疫耐受的非天然氨基酸，本课题组前期研究发现，将免疫原性氨基酸引入肿瘤相关抗原HER2中，在突破免疫耐受的同时还存在表位扩展现象，能诱导机体产生识别HER2不同位点的抗体。这种表位扩展现象为多途径阻断肿瘤免疫逃逸提供了新的思路。本项目拟对免疫原性氨基酸诱导自身抗原发生表位扩展的机制进行研究，设计筛选出能同时诱导机体产生抗HER2抗体和抗PD-L1抗体的双功能疫苗，通过阻断PD-1信号通路，解除肿瘤细胞对免疫效应细胞的抑制，形成正反馈，激活机体对HER2抗原的免疫效应，发挥抗肿瘤作用。本项目的顺利完成不仅可以为利用免疫原性氨基酸合理设计肿瘤疫苗提供理论指导，也为多途径阻断肿瘤免疫逃逸提供方法。

For a long time, blocking tumor immune escape of tumor vaccine design has been a challenge. As tumor cells can obtain ability of immune escape from a variety of pathways，such as immune tolerance and immune suppression，vaccine target to a single molecular is difficult to block immune escape of cancer cell effectively. .Immunogenic amino acid is a type of unnatural amino acid，which can make protein breakthrough autologous immune tolerance. Our previous study had proved that the introduction of an immunogenic amino acid into the tumor-associated antigen HER2 will break immune tolerance. Moreover，immunogenic amino acid can induce the body to produce antibodies to different sites of HER2. This epitope spreading phenomenon provides a new way for design vaccine to blocking tumor immune escape by multi-channel. The project intends to study on the mechanism of epitope spreading induced by immunogenic amino acid, and design bifunctional vaccine that can induce the body to produce an anti-HER2 antibody and anti-PD-L1 antibody simultaneously. Blocking the PD-1 signaling pathway could relieve inhibition of tumor cells to immune effector cells, and could form a positive feedback to active the immune response to HER2. The successful completion of this project not only provide theoretical guidance for the use of immunogenic amino acid rational design cancer vaccines, but also provided a method to multi-channel blocking tumor immune escape.