Synthesis And Immunological Properties Of TACA-based Anti-tumor Vaccines By Covalently Incorporating Th1 And Th2-type NKT Cell Agonists

Cancer is a major health diseases afflicting human. Traditional methods for cancer treatment include surgery, chemotherapy, radiation therapy and targeted therapies, the new strategies to harness the body's own immune system for prevention and treatment of cancer immunotherapy has attracted a lot of attention. The abnormal glycans expressing on the surface of tumor cells are called tumor-associated carbohydrate antigens (TACAs), they are valuable targets to develop carbohydrate-based anti-cancer vaccines. However, one of the major problems is that carbohydrate antigens alone can only evoke poor immunogenicity. How to trick the immune system to break tolerance and induce a response to tumor-associated carbohydrate antigens (TACAs), especially to elicit high titers of high-affinity IgG antibodies is a key problem remained to be solved in the field of TACA-based anti-cancer vaccine. The introduction of T-cell epitopes activated helper T cells is commonly used methods to improve antibody class switch from IgM to IgGRecent research shows that natural killer T (NKT) cells are a new type of T cells, functioning in a similar manner to helper T cells. We hypothesize that NKT cell agonist a-galactosyl ceramide (a-GalCer) and other glycosphingolipids covalently incorporated vaccine molecule, without the introduction of helper T cell epitope peptides, will contribute to the antibody type conversion from IgM to IgGSecretion of cytokines is essential for immunological activity of vaccine. Different a-GalCer analogs can stimulate NKT cells in the selective release of different types of cytokines, adjusting cytokine balance in immune system. The purpose of this paper is to study the correlation between cytokine selectivity and immunological activity of vaccine in which TACAs covalently link to a-GalCer and analogs.This dissertation described the synthesis of five different analogs of a-GalCer, which covalently attached to carbohydrate tumor antigen sTn. The immunological activities of the resultant four fully synthetic vaccine molecules were evaluated. The results show that vaccine containing Th1-type NKT cell agonist were able to induce higher IgG antibody than that of Th2-type agonist, but the absolute amount of IgG antibody produced by them were comparable to that of ?-GalCer, a weak NKT cell agonist. Further research remain to be done to investigate the correlation between cytokine selectivity and immunological activity of vaccine.