The Therapeutic Effect Of HPV16 E7 Vaccine And PD-1/PD-L1 Antibody On Mouse Cervical Cancer Model

Background:Persistent infection of human papillomavirus(HPV)is the main cause of cervical cancer.HPV is a double-stranded circular non-enveloped DNA virus whose genome encodes 6 early proteins(E1,E2,E4,E5,E6,E7)and 2 late proteins(L1,L2).As heterologous proteins,these molecules have become important targets for vaccine development.Some vaccines targeting L1 and L2 have been used in clinic.These vaccines are effective in reducing the risk of HPV infection in young women,but the situation is not optimistic for women in economically undeveloped areas and patients diagnosed with cervical cancer.Therefore,the development of HPV therapeutic vaccines is crucial.During the transformation of HPV-infected cells into cancer cells,HPV genes are integrated with human genome,and late genes may be lost,such as L1 and L2,but early proteins E6 and E7 are continuously expressed and play an important role in the process of transforming into cancer cells.Furthermore,studies showed that E7 has better immunogenicity than E6,so the development of vaccines specifically targeting E7 antigen has become an effective strategy.However,due to the low immunogenicity of E7 protein and its carcinogenic activity,there is no significant progress in related research.In recent years,with the further study of the functional structure of E7 protein,some E7 mutants without carcinogenic activity have been found.These mutants are useful for the development of vaccine.Adenovirus type 5 has been used as a vector in a variety of vaccines,and its safety and effectiveness have been confirmed.As a double stranded DNA virus,it is similar to a vaccine adjuvant and can effectively activate the recognition of human immune system.Programmed death ligand 1(PD-L1)on the surface of cancer cells can transmit inhibitory signals and cause T cell apoptosis after binding with programmed death ligand 1(PD-1)on the surface of activated T cells.PD-1/PD-L1 antibody or blocker can effectively inhibit the carcinogenesis induced by immune escape of cancer cells.Recently,PD-1/PD-L1 antibody or blocker has been applied to the treatment of a variety of cancers and worked well.In conclusion,the development of an E7 vaccine without oncogenic activity to activate the human immune system while effectively inhibiting tumor immune escape may become a effective strategy for the treatment of cervical cancer.Objective:To explore the therapeutic effect of a defective adenovirus vaccine expressing E7 mutant combined with PD-1/PD-L1 antibody in mouse cervical cancer tumor model.Methods:The TC-1 mouse tumor model was constructed as a cervical cancer model,and E7 vaccine and PD-1/PD-L1 antibody intervention were given.The effect of vaccine and antibody on tumor model was evaluated by detecting the proportion of related lymphocytes in spleen and tumor tissue,related cytokines in tumor and histological changes of tumor tissues.Conclusions:The constructed defective adenovirus vaccine expressing mutant E7(de1D21-C24)can effectively inhibit the growth of mouse tumors,increase the proportion of CD8+T cells,and inhibit the proliferation and invasion of tumors,but can not reduce the proportion of some immunosuppressive cells such as regulatory T cells(Treg)and myeloid derived suppressor cells(MDSC)in mice.When the vaccine combined with PD-1/PD-L1 antibody,the inhibitory effect on tumor growth was further enhanced.At the same time,it induced more CD8+T cells in mice,and significantly reduced the proportion of immunosuppressive cells in mice.In conclusion,our Ad-E7 vaccine can effectively inhibit the growth of mouse tumors,and the inhibitory effect is significantly higher when combined with PD-1/PD-L1 antibody.