Abstract
Human papilloma virus (HPV) 16 causes cervical cancer. Induction of oncogenesis by HPV 16 is primarily dependent on the function of E6 and E7 proteins, which inactivate the function of p53 and pRB, respectively. Thus, blocking the activity of the E6 and E7 proteins from HPV 16 is critical to inhibiting oncogenesis during infection. We have expressed and purified soluble HPV 16 E6 and E7 fusion immunoglobulin (Ig), which were combined with the constant region of an Ig heavy chain, in a mammalian system. To assess whether soluble E6 and E7 fusion Igs induce effective cellular immune responses, immature dendritic cells (DCs) were treated with these fusion proteins. Soluble E6 and E7 fusion Igs effectively induced maturation of DCs. Furthermore, immunization with soluble E6 and E7 fusion Igs in mice resulted in antigen-specific activation of T helper 1 (Th1) cells. This is the first comprehensive study to show the molecular basis of how soluble HPV 16 E6 or E7 fusion Igs induces Th1 responses through the maturation of DCs. In addition, we show that DC therapy using soluble HPV E6 and E7 fusion Igs may be a valuable tool for controlling the progress of cervical cancer.
Similar content being viewed by others
References
Astbury K, Turner MJ (2009) Human papillomavirus vaccination in the prevention of cervical neoplasia. Int J Gynecol Cancer 19:1610–1613
Chenais F, Virella G, Patrick CC, Fudenberg HH (1977) Isolation of soluble immune complexes by affinity chromatography using staphylococcal protein A-sepharose as substrate. J Immunol Meth 18:183–192
De Bruijn ML, Schuurhuis DH, Vierboom MP, Vermeulen H, de Cock KA, Ooms ME, Ressing ME, Toebes M, Franken KL, Drijfhout JW, Ottenhoff TH, Offringa R, Melief CJ (1998) Immunization with HPV16 oncoprotein-loaded dendritic cells as well as adjuvant induces MHC class I-restricted protection to HPV16-induced tumor cells. Cancer Res 58:724–731
Harro CD, Pang YY, Roden RB, Hildesheim A, Wang Z, Reynolds MJ, Mast TC, Robinson R, Murphy BR, Karron RA, Dillner J, Schiller JT, Lowy DR (2001) Safety and immunogenicity trial in adult volunteers of a human papillomarvirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 93:284–292
Hudson JB, Bedell MA, McCance DJ, Laiminis LA (1990) Immortalization and altered differentiation of human keratinocytes in vitro by the E6 and E7 open reading frames of human papillomavirus type 18. J Virol 64:519–526
Jin XW, Cash J, Kennedy AW (1999) Human papillomavirus typing and the reduction of cervical cancer risk. Cleve Clin J Med 66:533–539
Karanam B, Jagu S, Huh WK, Roden RB (2009) Devloping vaccines against minor capsid antigen L2 to prevent papillomavirus infection. Immunol Cell Biol 87:287–299
Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, Essahsah F, Fathers LM, Offringa R, Drijfhout JW, Wafelman AR, Oostendorp J, Fleuren GJ, van der Burg SH, Melief CJ (2009) Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. New Eng J Med 361:1838–1847
Kim SS, Byun HJ, Kim SH, Lee HH, Lee SJ, Kim SJ, Park CG, Chun T (2010) Soluble pig lymphocyte activation gene-3 (LAG-3; CD223) inhibits human-to-pig xenogeneic mixed lymphocyte reaction. Biotechnol Lett 32:203–208
Li J, Sun Y, Garen A (2002) Immunization and immunotherapy for cancers involving infection by a human papillomavirus in a mouse model. Proc Natl Acad Sci USA 99:16232–16236
Ling M, Kanayama M, Roden R, Wu TC (2000) Preventive and therapeutic vaccines for human papillomavirus-associated cervical cancers. J Biomed Sci 7:341–356
Liu M, Acres B, Balloul JM, Bizouarne N, Paul S, Slos P, Squiban P (2004) Gene-based vaccines and immunotherapeutics. Proc Natl Acad Sci USA 101:14567–14571
Murakami M, Gurski KJ, Marincola FM, Ackland J, Steller MA (1999) Induction of specific CD8+ T lymphocyte responses using a human papillomavirus-16 E6/E7 fusion protein and autologous dendritic cells. Cancer Res 59:1184–1187
Orth G, Favre M (1985) Human papillomaviruses. Biochemical and biologic properties. Clin Dermatol 3:27–42
Ory DS, Neugeboren BA, Mulligan RC (1996) A stable human-derived packaging cell line for production of high titer retrovirus/vesicular stomatitis virus G pseudotypes. Proc Natl Acad Sci USA 93:11400–11406
Robson NC, Hoves S, Maraskovsky E, Schnurr M (2010) Presentation of tumor antigens by dendritic cells and challenges faced. Curr Opin Immunol 22:137–144
Santin AD, Bellone S, Palmieri M, Zanolini A, Ravaggi A, Siegel ER, Roman JJ, Pecorelli S, Cannon MJ (2009) A novel CD4 T cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7 pulsed dendritic cells. Cancer Immunol Immunother 58:301–308
Syrjänen SM, Syrjänen KJ (1999) New concepts on the role of human papillomavirus in cell cycle regulation. Ann Med 31:175–187
Takeuchi O, Akira S (2009) Innate immunity to virus infection. Immunol Rev 227:75–86
van der Burg SH, Kwappenberg KM, O’Neill T, Brandt RM, Melief CJ, Hickling JK, Offringa R (2001) Pre-clinical safety and efficacy of TA-CIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens. Vaccine 19:3652–3660
Yan J, Harris K, Khan AS, Draghia-Akli R, Sewell D, Weiner DB (2008) Cellular immunity induced by a novel HPV18 DNA vaccine encoding an E6/E7 fusion consensus protein in mice and rhesus macaques. Vaccine 26:5210–5215
Yan J, Reichenbach DK, Corbitt N, Hokey DA, Ramanathan MP, Mckinney KA, Weiner DB, Sewell D (2009) Induction of antitumor immunity in vivo following delivery of a novel HPV-16 DNA vaccine encoding an E6/E7 fusion antigen. Vaccine 27:431–440
zur Hausen H (1999) Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 92:690–698
Acknowledgments
This work was supported by the National Research Foundation of Korea (NRF) grant (R01-2007-000-20475-0) funded by the Korea government (MEST) and was supported by a grant from the Korea Health 21 R & D Project, Ministry of Health & Welfare, Republic of Korea (Project Number: A040004).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Kim, SH., Hur, Y.J., Lee, S.J. et al. E6 and E7 fusion immunoglobulin from human papilloma virus 16 induces dendritic cell maturation and antigen specific activation of T helper 1 response. Biotechnol Lett 33, 663–671 (2011). https://doi.org/10.1007/s10529-010-0489-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10529-010-0489-0