Characterization of HPV18 E6-specific T cell responses and establishment of HPV18 E6-expressing tumor model |
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| Institution: | 1. Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Centre, Copenhagen, Denmark;2. Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen, Denmark;3. Department of ORL, H&N surgery and audiology, Rigshospitalet, Copenhagen University Hospital, Denmark;4. Department of Gynecology, Rigshospitalet, Copenhagen University Hospital, Denmark;1. Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, Atlanta, GA, United States;2. Northrup Grumman, Atlanta, GA, United States;3. Division of Sexually Transmitted Disease Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, United States;4. Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, United States;5. Los Angeles County Cancer Surveillance Program, Los Angeles, CA, United States;6. Louisiana Tumor Registry, Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, United States;7. Michigan Cancer Surveillance Program, Lansing, MI, United States;8. Kentucky Cancer Registry, Lexington, KY, United States;9. Advanced Technical Logistics, Inc., Newnan, GA, United States |
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| Abstract: | Human papillomavirus (HPV) has been identified as the primary etiologic factor of cervical cancer, and subsets of anogenital and oropharyngeal cancers. HPV18 is the second most prevalent high-risk HPV type after HPV16. Furthermore, HPV18 is responsible for approximately 12% of cervical squamous cell carcinoma and 37% of cervical adenocarcinoma cases worldwide. In this study, we aimed to characterize the HPV18-E6-specific epitope and establish an HPV18 animal tumor model to evaluate the E6-specific immune response induced by our DNA vaccine. We vaccinated naïve C57BL/6 mice with a prototype DNA vaccine, pcDNA3-HPV18-E6, via intramuscular injection followed by electroporation, and analyzed the E6-specific CD8+ T cell responses by flow cytometry using a reported T cell epitope. We then characterized the MHC restriction element for the characterized HPV18-E6 epitope. Additionally, we generated an HPV18-E6-expressing tumor cell line to study the antitumor effect mediated by E6-specific immunity. We observed a robust HPV18-E6aa67-75 peptide-specific CD8+ T cell response after vaccination with pcDNA3-HPV18-E6. Further characterization demonstrated that this epitope was mainly restricted by H-2Kb, but was also weakly presented by HLA-A10201, as previously reported. We observed that vaccination with pcDNA3-HPV18-E6 significantly inhibited the growth of HPV18-E6-expressing tumor cells, TC-1/HPV18-E6, in mice. An antibody depletion study demonstrated that both CD4+ and CD8+ T cells are necessary for the observed antitumor immunity. The characterization of HPV18-E6-specific T cell responses and the establishment of HPV18-E6-expressing tumor cell line provide infrastructures for further development of HPV18-E6 targeted immunotherapy. |
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| Keywords: | Human papillomavirus 18 E6 oncoprotein DNA vaccine Immunotherapy HPV18-E6 tumor model |
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