Enhancing Antitumor Immunogenicity of HPV16-E7 DNA Vaccine by Fusing DNA Encoding E7-antigenic Peptide to DNA Encoding Capsid Protein L1 of Bovine Papillomavirus

Overview

Journal Cell Biosci

Publisher Biomed Central

Specialty Biology

Date 2017 Aug 31

PMID 28852471

Citations 5

Authors

Andrew Yang

Shiwen Peng

Emily Farmer

Qi Zeng

Max A Cheng

Xiaowu Pang

T-C Wu

Chien-Fu Hung

Affiliations

Soon will be listed here.

Abstract

Background: Human papillomavirus (HPV) has been identified as the primary etiologic factor of cervical cancer, the fourth leading cause of cancer death in females worldwide. We have previously shown that coadministration of DNA encoding L1 capsid protein of Bovine papillomavirus (BPV) can enhance the antigen-specific immune response elicited by a therapeutic HPV16-E7 DNA vaccination. In this study, we sought to generate and evaluate the immunogenicity of a therapeutic HPV16-E7 DNA vaccine that encodes the fusion construct of HPV16-E7 and BPV-L1.

Results: We generated a therapeutic HPV16-E7 DNA vaccine construct, pcDNA3-BPVL1-E7(49-57), encoding the fusion sequence of full-length BPVL1 protein and a murine E7 antigenic epitope, aa49-57. Transfecting 293-D cells with pcDNA3-BPVL1-E7(49-57) demonstrated that this DNA construct can effectively lead to the presentation of E7 epitope for the activation of E7-specific CD8+ T cells in vitro. Intramuscular vaccination of pcDNA3-BPVL1-E7(49-57) with electroporation generated a stronger E7-specific CD8+ T cell-mediated immune response than coadministration of pcDNA3-BPVL1 and pcDNA3-E7(49-57) in C57BL/6 mice. Furthermore, we observed that the strong E7-specific CD8+ T cell response elicited by pcDNA3-BPVL1-E7(49-57) vaccination translated into potent protective and therapeutic antitumor effects in C57BL/6 mice against HPV16-E7 expressing TC-1 tumor cells. Finally, using antibody depletion experiment, we showed that the antitumor immune response generated by pcDNA3-BPVL1-E7(49-57) is CD8+ T cell dependent, and CD4+ T cell and NK cell independent.

Conclusion: Treatment with fusion construct of BPV-L1 and HPV16-E7 epitope can elicit effective E7-specific antitumor immune response in mice. Due to the potential ability of the fusion DNA construct to also trigger immune responses specific to the L1 protein, the current study serves to support future design of HPV DNA vaccines encoding fusion HPVL1-E6/E7 constructs for the generation of both T cell and B cell mediated immune responses against HPV infections and associated diseases.

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References

Zhai Y, Zhong Z, Zariffard M, Spear G, Qiao L . Bovine papillomavirus-like particles presenting conserved epitopes from membrane-proximal external region of HIV-1 gp41 induced mucosal and systemic antibodies. Vaccine. 2013; 31(46):5422-9. PMC: 3881962. DOI: 10.1016/j.vaccine.2013.09.003. View

Gupta G, Glueck R, Patel P . HPV vaccines: Global perspectives. Hum Vaccin Immunother. 2017; 13(6):1-4. PMC: 5489288. DOI: 10.1080/21645515.2017.1289301. View

Yang B, Yang A, Peng S, Pang X, Roden R, Wu T . Co-administration with DNA encoding papillomavirus capsid proteins enhances the antitumor effects generated by therapeutic HPV DNA vaccination. Cell Biosci. 2015; 5:35. PMC: 4480891. DOI: 10.1186/s13578-015-0025-y. View

Lenz P, Day P, Pang Y, FRYE S, JENSEN P, Lowy D . Papillomavirus-like particles induce acute activation of dendritic cells. J Immunol. 2001; 166(9):5346-55. DOI: 10.4049/jimmunol.166.9.5346. View

Schellenbacher C, Roden R, Kirnbauer R . Developments in L2-based human papillomavirus (HPV) vaccines. Virus Res. 2016; 231:166-175. PMC: 5549463. DOI: 10.1016/j.virusres.2016.11.020. View

Peng S, Frazer I, Fernando G, Zhou J . Papillomavirus virus-like particles can deliver defined CTL epitopes to the MHC class I pathway. Virology. 1998; 240(1):147-57. DOI: 10.1006/viro.1997.8912. View

Kim D, Gambhira R, Karanam B, Monie A, Hung C, Roden R . Generation and characterization of a preventive and therapeutic HPV DNA vaccine. Vaccine. 2007; 26(3):351-60. PMC: 2258233. DOI: 10.1016/j.vaccine.2007.11.019. View

Roldao A, Mellado M, Castilho L, Carrondo M, Alves P . Virus-like particles in vaccine development. Expert Rev Vaccines. 2010; 9(10):1149-76. DOI: 10.1586/erv.10.115. View

Yang R, Martinez Murillo F, Cui H, Blosser R, Uematsu S, Takeda K . Papillomavirus-like particles stimulate murine bone marrow-derived dendritic cells to produce alpha interferon and Th1 immune responses via MyD88. J Virol. 2004; 78(20):11152-60. PMC: 521855. DOI: 10.1128/JVI.78.20.11152-11160.2004. View

10.

Song L, Yang M, Knoff J, Wu T, Hung C . Cancer immunotherapy employing an innovative strategy to enhance CD4+ T cell help in the tumor microenvironment. PLoS One. 2014; 9(12):e115711. PMC: 4274108. DOI: 10.1371/journal.pone.0115711. View

11.

Peng S, Mattox A, Best S, Barbu A, Burns J, Akpeng B . Identification of the murine H-2D(b) and human HLA-A*0201 MHC class I-restricted HPV6 E7-specific cytotoxic T lymphocyte epitopes. Cancer Immunol Immunother. 2016; 65(3):261-71. PMC: 5690558. DOI: 10.1007/s00262-016-1793-x. View

12.

Zhang H, Huang Y, Fayad R, Spear G, Qiao L . Induction of mucosal and systemic neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) by oral immunization with bovine Papillomavirus-HIV-1 gp41 chimeric virus-like particles. J Virol. 2004; 78(15):8342-8. PMC: 446118. DOI: 10.1128/JVI.78.15.8342-8348.2004. View

13.

Hung C, Cheng W, He L, Ling M, Juang J, Lin C . Enhancing major histocompatibility complex class I antigen presentation by targeting antigen to centrosomes. Cancer Res. 2003; 63(10):2393-8. View

14.

Wu T, Guarnieri F, Staveley-OCarroll K, Viscidi R, Levitsky H, Hedrick L . Engineering an intracellular pathway for major histocompatibility complex class II presentation of antigens. Proc Natl Acad Sci U S A. 1995; 92(25):11671-5. PMC: 40464. DOI: 10.1073/pnas.92.25.11671. View

15.

Orzalli M, Knipe D . Cellular sensing of viral DNA and viral evasion mechanisms. Annu Rev Microbiol. 2014; 68:477-92. PMC: 4348004. DOI: 10.1146/annurev-micro-091313-103409. View

16.

Yim E, Park J . The role of HPV E6 and E7 oncoproteins in HPV-associated cervical carcinogenesis. Cancer Res Treat. 2009; 37(6):319-24. PMC: 2785934. DOI: 10.4143/crt.2005.37.6.319. View

17.

Lin K, Guarnieri F, Staveley-OCarroll K, Levitsky H, August J, Pardoll D . Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res. 1996; 56(1):21-6. View

18.

Munoz N, Bosch F, de Sanjose S, Herrero R, Castellsague X, Shah K . Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003; 348(6):518-27. DOI: 10.1056/NEJMoa021641. View

19.

Hung C, He L, Juang J, Ling M, Wu T . Improving DNA vaccine potency by linking Marek's disease virus type 1 VP22 to an antigen. J Virol. 2002; 76(6):2676-82. PMC: 135982. DOI: 10.1128/jvi.76.6.2676-2682.2002. View

20.

Hung C, Hsu K, Cheng W, Chai C, He L, Ling M . Enhancement of DNA vaccine potency by linkage of antigen gene to a gene encoding the extracellular domain of Fms-like tyrosine kinase 3-ligand. Cancer Res. 2001; 61(3):1080-8. View