Preparation And Immunological Evaluation Of Fully Synthetic MUC1-Based Anticancer Vaccine

Immunotherapy plays an important role in the treatment of cancer while vaccines play an important role in immunotherapy.Compared with traditional vaccines,chemosynthetic vaccines have the advantages of uniform components and definite structure,and thus become a research hotspot.For chemosynthetic vaccines,it is important to find specific effective antigens and design efficient vaccine system.The membrane-bound tumorassociated glycoprotein MUC1 is aberrantly glycosylated in cancer cells compared with normal cells,and therefore considered as an attractive target for cancer immunotherapy.However,the tumor-associated glycopeptides MUC1 do not elicit a sufficiently robust immune response.To solve this problem,researchers are increasingly interested in improving the immunogenicity of MUC1 to give effective anticancer vaccines,such as the conjugates of MUC1 antigen and carrier protein or different immune stimulants.For the purpose of this study,the focus that remain to be solved are to overcome the poor immunogenicity of MUC1 antigens to induce high anti-MUC1 IgG titers.Our previous work shows that:tumour-associated carbohydrate antigen was constructed with the NKT cell agonist αGalCer and showed remarkable efficacy and induced antibody class switching from IgM to IgG.This word use MUC1 to design different antigens and NKT cell agonist aGalCer was used as an adjuvant to prepare vaccines for mouse immunization,use T-helper and αGalCer to optimize vaccine activity.We hypothesize that these factors are closely related to the innate and adaptive immune responses of the vaccine against tumor and need to be studied through a detailed structure-activity relationship.This paper is divided into three chapters.The main contents of each chapter are as follows:The first chapter introduces the research background and the basis of the topic.Including cancer and immunotherapy、the research progress of MUC1、the research progress of aGalCer.Finally,the topic of this paper is proposed:to solve the problem of poor immunogenicity of MUC1,and to design a glycopeptide anti-tumor vaccine targeting MUC1,which can obtain IgG antibody with high affinity in mouse immunity.The second chapter mainly studies the interaction between different adjuvants and the targeted MUC1 antigen was compared and the effect of different antigen structure on vaccine efficacy.The main work of this chapter is:(1)Fully synthesis of MUC1-targeted glycopeptide anti-tumor vaccine;(2)Preparation of liposome vaccine and mouse immunity;(3)Study on the biological activity of MUC1-targeted glycopeptide anti-tumor vaccine.The results of this study showed that the covalently linked antigen of the T-epitope peptide and MUC1 fragment had positive interaction with the αGalCer.It can be used to prepare strong and effective polypeptide anti-tumor vaccine.The third chapter mainly studies the interaction between different T-epitope peptides and MUC1 covalently linked antigens with αGalCer.The result shows PV and MUC1 Vaccine works best.In this study,a novel nano-liposome vaccine was used to generate IgG antibody with high affinity in mouse immunity by physical mixing of NKT cell agonist αGalCer as adjuvant.This study provides a new strategy for the design of MUC1 anti-tumor vaccine and a new direction for the application of NKT cell agonist aGalCer.