Enhancing The Antitumor Immunity Of DNA Vaccine In A Murine Cervical Cancer Model By Combining The Use Of LIGHT DNA

Despite great achievements in the prevention and treament of cervical cancer and premalignant disease, the worldwide morbidity and mortality of cervical cancer is still very high. Supplementation of the traditional therapeutics by immunotherapies will become a promising one. As we all know, human papillomaviruses (HPV) infecton is a necessary cause of cervical cancer, and the viral early proteins E6 and/or E7 is also necessary to maintain the malignant phenotype of cervical cancer cells, so that is to say, cervical cancer tissues can be always expressing viral proteins. And those proteins are derived from the virus, so they have the immunogenecity and they have the potential to become perfect target antigens of immunotherapies. Therefore, various kinds of therapeutic vaccines have been developed, including protein vaccine, DNA vaccine, peptide vaccine, viral vector vaccine, bacterial vector vaccine, DC-based vaccine and tumor cell-based vaccine. A variety of clinical trials have been performed to test the efficiency of these vaccines. Although a specific anti-HPV T cell response in patients can be detected, the inhibition of tumor growth is not obvious. This can probably be attributed to immunosuppressive environment in the tumor sites.DNA vaccines have become an attractive approach for generating antigen-specific immunotherapy in view of the ease to produce, store and transport. Various strategies have been developed to enhance their immunogenecity. LIGHT, also known as TNFSF14, is believed to overcome tumour immune suppression by generating a dominantly pro-inflammatory environment. An interesting unresolved question is whether LIGHT-mediated tumor environment can work synergistically with DNA vaccine. To address this issue, we constructed a eukaryotic expression plasmid (pcDNA3.1-LIGHT) by inserting mouse LIGHT gene into the vector pcDNA3.1 (+). The data in this study showed that treatment by injection of LIGHT resulted in down-regulation of Th2 and Treg cytokines and promotion of dendritic cell maturation and activation, but the adaptive antitumor immune responses achieved by LIGHT administration alone were limited. Then, we evaluated the immunotherapeutic efficacy and mechanism of combination therapy of HPV16 E7 DNA vaccine/LIGHT by using a murine cervical cancer model. Our in vivo studies revealed that treatment with HPV16 E7 DNA vaccine alone did not lead to satisfactory tumor growth inhibition, whereas cotreatment with LIGHT significantly improved antitumor immunity and compensated the deficiency of HPV16 E7 DNA vaccine by increasing the expression of Th1 cytokines, IL-2, and IFN-γand decreasing the expression of immunosuppressive factors, IL-10, TGF-β, and Foxp3 in the tumor microenvironment. HPV16 E7 DNA vaccine/LIGHT in combination with cisplatin exhibited an even more effective antitumor response. HPV16 E7 DNA vaccine/LIGHT also exibited some tumor provention efficacy. Taken together, our findings indicate that enhanced LIGHT expression results in a significant synergistic effect against tumor cells both therapeutically and preventively in vivo when combined with the HPV16 E7 DNA vaccine and LIGHT may be an effective immunological adjuvant in DNA vaccination.