Advertisement

Archives of Virology

, Volume 159, Issue 8, pp 1951–1960 | Cite as

Comparing the effect of Toll-like receptor agonist adjuvants on the efficiency of a DNA vaccine

  • Azadeh Sajadian
  • Alijan Tabarraei
  • Hoorieh Soleimanjahi
  • Fatemeh Fotouhi
  • Ali Gorji
  • Amir GhaemiEmail author
Original Article

Abstract

We have investigated whether poly(I:C) Toll-like receptor 3 (TLR3) and resiquimod Toll-like receptor 7 (TLR7) agonists can serve as vaccine adjuvants and promote the efficiency of therapeutic DNA vaccination against tumors expressing the human papilloma virus 16 (HPV-16) E7 protein. For this purpose, C57BL/6 mice were inoculated with 2 × 105 TC-1 cells, and they were then immunized with HPV-16 E7 DNA vaccine alone or with 50 μg of resiquimod or poly(I:C) individually. We found that poly(I:C) and resiquimod could induce more antigen-specific lymphocyte proliferation and cytolytic activity compared to vaccination with E7 DNA alone. While E7 DNA had no significant inhibitory effect on tumor growth, co-administration of poly(I:C) and resiquimod with E7 DNA induced significant tumor regression. Peripheral and local cytokine assays demonstrated that co-administration of poly(I:C) and resiquimod with E7 DNA induced circulating antigen-specific IFN-γ and nonspecific intratumoral IL-12. TLR3 and TLR7 agonists can be used to enhance the immune response to DNA vaccine immunogens. Taken together, these data indicate that combined vaccination with DNA encoding HPV-16 E7 plus TLR agonists provides a strategy for improving the efficacy of a vaccine as a possible immunotherapeutic strategy for cervical cancer.

Keywords

Human Papilloma Virus Imiquimod Vaccine Adjuvant Resiquimod Tumor Treatment Experiment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

HPV

Human papilloma virus

TLR

Toll-like receptor

PHA

Phytohemagglutinin

APC

Antigen-presenting cell

CTL

Cytolytic T lymphocyte

DC

Dendritic cell

FDA

Food and Drug Administration

IFN- γ

Interferon γ

IL-4

Interleukin 4

IL-10

Interleukin 10

IL-12

Interleukin 12

PMSF

Phenylmethanesulfonyl fluoride

LDH

Lactate dehydrogenase

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

OD

Optical density

FCS

Fetal calf serum

RPMI

1640 Roswell Park Memorial Institute (name of the medium)

Th

T helper

Notes

Funding

This study was supported by Golestan University of Medical Sciences, Gorgan, Iran.

Disclosure

All the authors declare that they have no conflicting interests.

References

  1. 1.
    WHO/ICO HPV Information Centre (2010) Human papillomavirus and related cancers in world. Summary Report 2010 WHOGoogle Scholar
  2. 2.
    Adams M, Navabi H, Jasani B, Man S, Fiander A, Evans AS, Donninger C, Mason M (2003) Dendritic cell (DC) based therapy for cervical cancer: use of DC pulsed with tumour lysate and matured with a novel synthetic clinically non-toxic double stranded RNA analogue poly [I]:poly [C(12)U] (Ampligen R). Vaccine 21:787–790PubMedCrossRefGoogle Scholar
  3. 3.
    Adams S (2009) Toll-like receptor agonists in cancer therapy. Immunotherapy 1:949–964PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738PubMedCrossRefGoogle Scholar
  5. 5.
    Brugnolo F, Sampognaro S, Liotta F, Cosmi L, Annunziato F, Manuelli C, Campi P, Maggi E, Romagnani S, Parronchi P (2003) The novel synthetic immune response modifier R-848 (Resiquimod) shifts human allergen-specific CD4+ TH2 lymphocytes into IFN-gamma-producing cells. J Allergy Clin Immunol 111:380–388PubMedCrossRefGoogle Scholar
  6. 6.
    Cheng YS, Xu F (2010) Anticancer function of polyinosinic-polycytidylic acid. Cancer Biol Ther 10:1219–1223PubMedCrossRefGoogle Scholar
  7. 7.
    Chuang CM, Monie A, Hung CF, Wu TC (2010) Treatment with imiquimod enhances antitumor immunity induced by therapeutic HPV DNA vaccination. J Biomed Sci 17:32PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Dias CC, Moraes MP, Weiss M, Diaz-San Segundo F, Perez-Martin E, Salazar AM, de los Santos T, Grubman MJ (2012) Novel antiviral therapeutics to control foot-and-mouth disease. J Interferon Cytokine Res 32:462–473PubMedCrossRefGoogle Scholar
  9. 9.
    Dumitru CD, Antonysamy MA, Gorski KS, Johnson DD, Reddy LG, Lutterman JL, Piri MM, Proksch J, McGurran SM, Egging EA, Cochran FR, Lipson KE, Tomai MA, Gullikson GW (2009) NK1.1+ cells mediate the antitumor effects of a dual Toll-like receptor 7/8 agonist in the disseminated B16-F10 melanoma model. Cancer Immunol Immunother 58:575–587PubMedCrossRefGoogle Scholar
  10. 10.
    Fidock MD, Souberbielle BE, Laxton C, Rawal J, Delpuech-Adams O, Corey TP, Colman P, Kumar V, Cheng JB, Wright K, Srinivasan S, Rana K, Craig C, Horscroft N, Perros M, Westby M, Webster R, van der Ryst E (2011) The innate immune response, clinical outcomes, and ex vivo HCV antiviral efficacy of a TLR7 agonist (PF-4878691). Clin Pharmacol Ther 89:821–829PubMedCrossRefGoogle Scholar
  11. 11.
    Fife KH, Meng TC, Ferris DG, Liu P (2008) Effect of resiquimod 0.01% gel on lesion healing and viral shedding when applied to genital herpes lesions. Antimicrob Agents Chemother 52:477–482PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Ghaemi A, Soleimanjahi H, Gill P, Hassan Z, Jahromi SR, Roohvand F (2010) Recombinant lambda-phage nanobioparticles for tumor therapy in mice models. Genet Vaccines Ther 8:3PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Ghaemi A, Soleimanjahi H, Gill P, Hassan ZM, Razeghi S, Fazeli M, Razavinikoo SM (2011) Protection of mice by a lambda-based therapeutic vaccine against cancer associated with human papillomavirus type 16. Intervirology 54:105–112PubMedCrossRefGoogle Scholar
  14. 14.
    Gibson SJ, Lindh JM, Riter TR, Gleason RM, Rogers LM, Fuller AE, Oesterich JL, Gorden KB, Qiu X, McKane SW, Noelle RJ, Miller RL, Kedl RM, Fitzgerald-Bocarsly P, Tomai MA, Vasilakos JP (2002) Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. Cell Immunol 218:74–86PubMedCrossRefGoogle Scholar
  15. 15.
    Gnjatic S, Sawhney NB, Bhardwaj N (2010) Toll-like receptor agonists: are they good adjuvants? Cancer J (Sudbury, Mass) 16:382–391CrossRefGoogle Scholar
  16. 16.
    Guy B (2007) The perfect mix: recent progress in adjuvant research. Nat Rev Microbiol 5:505–517PubMedCrossRefGoogle Scholar
  17. 17.
    Huang B, Mao CP, Peng S, He L, Hung CF, Wu TC (2007) Intradermal administration of DNA vaccines combining a strategy to bypass antigen processing with a strategy to prolong dendritic cell survival enhances DNA vaccine potency. Vaccine 25:7824–7831PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Huang CY, Chen JJ, Shen KY, Chang LS, Yeh YC, Chen IH, Chong P, Liu SJ, Leng CH (2012) Recombinant lipidated HPV E7 induces a Th-1-biased immune response and protective immunity against cervical cancer in a mouse model. PloS One 7:e40970PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Ito T, Amakawa R, Kaisho T, Hemmi H, Tajima K, Uehira K, Ozaki Y, Tomizawa H, Akira S, Fukuhara S (2002) Interferon-alpha and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets. J Exp Med 195:1507–1512PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Lin K, Roosinovich E, Ma B, Hung CF, Wu TC (2010) Therapeutic HPV DNA vaccines. Immunol Res 47:86–112PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Longhi MP, Trumpfheller C, Idoyaga J, Caskey M, Matos I, Kluger C, Salazar AM, Colonna M, Steinman RM (2009) Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med 206:1589–1602PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Marquez JP, Rivera R, Kang KH, Gardner MB, Torres JV (2012) Human papillomavirus immunogen that provides protective tumor immunity and induces tumor regression. Viral Immunol 25:141–152PubMedCrossRefGoogle Scholar
  23. 23.
    McLaughlin-Drubin ME, Munger K (2009) The human papillomavirus E7 oncoprotein. Virology 384:335–344PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Munoz N, Bosch FX, Castellsague X, Diaz M, de Sanjose S, Hammouda D, Shah KV, Meijer CJ (2004) Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 111:278–285PubMedCrossRefGoogle Scholar
  25. 25.
    Navabi H, Jasani B, Reece A, Clayton A, Tabi Z, Donninger C, Mason M, Adams M (2009) A clinical grade poly I:C-analogue (Ampligen) promotes optimal DC maturation and Th1-type T cell responses of healthy donors and cancer patients in vitro. Vaccine 27:107–115PubMedCrossRefGoogle Scholar
  26. 26.
    Otero M, Calarota SA, Felber B, Laddy D, Pavlakis G, Boyer JD, Weiner DB (2004) Resiquimod is a modest adjuvant for HIV-1 gag-based genetic immunization in a mouse model. Vaccine 22:1782–1790PubMedCrossRefGoogle Scholar
  27. 27.
    Pasare C, Medzhitov R (2004) Toll-like receptors: linking innate and adaptive immunity. Microbes Infect 6:1382–1387PubMedCrossRefGoogle Scholar
  28. 28.
    Pulendran B (2005) Variegation of the immune response with dendritic cells and pathogen recognition receptors. J Immunol (Baltimore, Md : 1950) 174:2457–2465CrossRefGoogle Scholar
  29. 29.
    Qin H, Cha SC, Neelapu SS, Lou Y, Wei J, Liu YJ, Kwak LW (2009) Vaccine site inflammation potentiates idiotype DNA vaccine-induced therapeutic T cell-, and not B cell-, dependent antilymphoma immunity. Blood 114:4142–4149PubMedCrossRefGoogle Scholar
  30. 30.
    Saade F, Petrovsky N (2012) Technologies for enhanced efficacy of DNA vaccines. Expert Rev Vaccines 11:189–209PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T (2006) TLR3 can directly trigger apoptosis in human cancer cells. J Immunol (Baltimore, Md : 1950) 176:4894–4901CrossRefGoogle Scholar
  32. 32.
    Salaun B, Lebecque S, Matikainen S, Rimoldi D, Romero P (2007) Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clin Cancer Res 13:4565–4574PubMedCrossRefGoogle Scholar
  33. 33.
    Salaun B, Zitvogel L, Asselin-Paturel C, Morel Y, Chemin K, Dubois C, Massacrier C, Conforti R, Chenard MP, Sabourin JC, Goubar A, Lebecque S, Pierres M, Rimoldi D, Romero P, Andre F (2011) TLR3 as a biomarker for the therapeutic efficacy of double-stranded RNA in breast cancer. Cancer Res 71:1607–1614PubMedCrossRefGoogle Scholar
  34. 34.
    Schulz O, Diebold SS, Chen M, Naslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljestrom P, Reis e Sousa C (2005) Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433:887–892PubMedCrossRefGoogle Scholar
  35. 35.
    Su JH, Wu A, Scotney E, Ma B, Monie A, Hung CF, Wu TC (2010) Immunotherapy for cervical cancer: research status and clinical potential. BioDrugs 24:109–129PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Tewari K, Flynn BJ, Boscardin SB, Kastenmueller K, Salazar AM, Anderson CA, Soundarapandian V, Ahumada A, Keler T, Hoffman SL, Nussenzweig MC, Steinman RM, Seder RA (2010) Poly(I:C) is an effective adjuvant for antibody and multi-functional CD4+ T cell responses to Plasmodium falciparum circumsporozoite protein (CSP) and alphaDEC-CSP in non human primates. Vaccine 28:7256–7266PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Trumpfheller C, Longhi MP, Caskey M, Idoyaga J, Bozzacco L, Keler T, Schlesinger SJ, Steinman RM (2012) Dendritic cell-targeted protein vaccines: a novel approach to induce T-cell immunity. J Intern Med 271:183–192PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Wille-Reece U, Wu CY, Flynn BJ, Kedl RM, Seder RA (2005) Immunization with HIV-1 Gag protein conjugated to a TLR7/8 agonist results in the generation of HIV-1 Gag-specific Th1 and CD8+ T cell responses. J Immunol (Baltimore, Md: 1950) 174:7676–7683CrossRefGoogle Scholar
  39. 39.
    Yu L, Chen S (2008) Toll-like receptors expressed in tumor cells: targets for therapy. Cancer Immunol Immunother 57:1271–1278PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Azadeh Sajadian
    • 1
  • Alijan Tabarraei
    • 2
  • Hoorieh Soleimanjahi
    • 3
  • Fatemeh Fotouhi
    • 4
  • Ali Gorji
    • 1
    • 5
    • 6
    • 7
  • Amir Ghaemi
    • 2
    • 8
    Email author
  1. 1.Shefa Neuroscience Research CenterTehranIran
  2. 2.Department of MicrobiologyGolestan University of Medical SciencesGorganIran
  3. 3.Department of Virology, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran
  4. 4.Department of VirologyPasteur Institute of IranTehranIran
  5. 5.Institut für Physiologie I, Westfälische Wilhelms-Universität MünsterMünsterGermany
  6. 6.Klinik und Poliklinik für Neurochirurgie, Westfälische Wilhelms-Universität MünsterMünsterGermany
  7. 7.Department of neurologyWestfälische Wilhelms-Universität MünsterMünsterGermany
  8. 8.Shefa Neuroscience Research Center, Khatam Al-Anbiya HospitalTehranIran

Personalised recommendations