자궁경부암 HPV E7 유전자 백신의 조작에 의한 종양 백신역가의 변화
Enhancement of E7 DNA Vaccine potency by antigen engineering and coinjection with IL-12 Genes in an animal model
자경경부암 종양 백신;
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Infection with human papillomavirus (HPV) types 16 and 18 is the major cause of cervical cancer in women nationwide. Presently, many studies are on going in order to develop both prophylactic and therapeutic strategies against cervical cancer. However, aside from present therapy modalities including radical surgery, radiation and chemo-based approaches, other therapy modalities against cervical cancer are still demanding. In this regard, immune-based approaches have been studied using tumor-specific proteins, peptides, virus vectors and naked DNA vaccines. In particular, DNA immunization is a new approach for cancer immune therapy. However, its weakness in potency has been problematic. In this study, we constructed different cassettes of human papillomavirus (HPV) 16 E7 expression vectors and then evaluated their efficacy for protection against HPV 16 E7-expressing tumor challenge in an animal model. When delivered in a DNA form, wild type E7 antigens showed little protection from tumor challenge in a manner similar to negative controls. However, secreted, cell membrane-targeted and endosome/lysosome targeted E7 antigens displayed an augmentation in tumor protection (tumor growth rate: negative control and wild type E7, 90%; Sig/E7, 0%; Sig/E7/TMR, 30%; Sig/E7/LAMP, 0%). When re-challenged with 20-fold more tumor cells, endosome/lysosome targeted E7 antigens (Sig/E7/LAMP) and to a lesser degree secreted E7 antigens (Sig/E7) resulted in regression of tumor rechallenge. Primary protection pattern was also observed similarly when endosome/lysosome targeted E7 and secreted E7 antigens were compared for protective immunity against TC-1 tumor challenge. This suggests that the cellular location of E7 antigens, in particular location of antigens to the endosome/lysosome compartment plays an important role in induction of primary and memory protective immunity against tumor challenge. Anti-tumor protection mechanism(s) appeared to be mediated by IFN- releasing CD8+ T cells (CTL marker), as determined by in vivo CD8+ T cell subset depletion and IFN- production profile. Furthermore, coinjection of E7 DNA vaccine along with IL-12 genes resulted in an increase in protection from tumor growth at the prophylactic and therapeutic levels. Taken together, our data suggest that both tailored modification of E7 antigens and coinjection of IL-12 genes are positively related to vaccine potency for cancer immune therapy.