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Differential immune responses mediated by adenovirus- and lentivirus-transduced DCs in a HER-2/neu overexpressing tumor model

Gene Therapy volume 18, pages 986–995 (2011)Cite this article

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Abstract

Recent investigations have demonstrated that adenoviral and lentiviral vectors encoding HER-2 can be utilized in cancer immunotherapy. However, it is not known whether both viral systems elicit a similar immune response. Here, we compare the immune response in mice induced by dendritic cells (DCs) infected with either recombinant adenovirus or lentivirus encoding rat HER-2 (rHER-2). Both vaccine types yielded similar control of tumor growth, but we found clear differences in their immune responses 10 days after DC immunization. Adenovirus rHER-2-transduced DCs elicited locally and systemically high frequencies of CD4+ and CD8+ T cells, while lentivirus rHER-2-transduced DCs predominantly led to CD4+ T-cell infiltration at the tumor site. Splenocytes from mice immunized with lentivirus rHER-2-transduced DCs secreted higher levels of interferon (IFN)-γ, mainly by CD4+ T cells, following stimulation by RM-1-mHER-2 tumors. In contrast, the adenovirus vaccinated group exhibited CD4+ and CD8+ T cells that both contributed to IFN-γ production. Besides an established cellular immune response, the rHER-2/DC vaccine elicited a significant humoral response that was highest in the adenovirus group. DC subsets and regulatory T cells in the spleen were also differentially modulated in the two vaccine systems. Finally, adoptive transfer of splenocytes from both groups of immunized mice strongly inhibited in vivo tumor growth. Our results suggest that not only the target antigen but also the virus system may determine the nature and magnitude of antitumor immunity by DC vaccination.

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References

  1. Disis ML, Knutson KL, Schiffman K, Rinn K, McNeel DG . Pre-existent immunity to the HER-2/neu oncogenic protein in patients with HER-2/neu overexpressing breast and ovarian cancer. Breast Cancer Res Treat 2000; 62: 245–252.

    Article  CAS  PubMed  Google Scholar 

  2. Fendly BM, Kotts C, Vetterlein D, Lewis GD, Winget M, Carver ME et al. The extracellular domain of HER2/neu is a potential immunogen for active specific immunotherapy of breast cancer. J Biol Response Mod 1990; 9: 449–455.

    CAS  PubMed  Google Scholar 

  3. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M . Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001; 93: 1852–1857.

    Article  CAS  PubMed  Google Scholar 

  4. Mossoba ME, Medin JA . Cancer immunotherapy using virally transduced dendritic cells: animal studies and human clinical trials. Expert Rev Vaccines 2006; 5: 717–732.

    Article  CAS  PubMed  Google Scholar 

  5. Loisel-Meyer S, Foley R, Medin JA . Immuno-gene therapy approaches for cancer: from in vitro studies to clinical trials. Front Biosci 2008; 13: 3202–3214.

    Article  CAS  PubMed  Google Scholar 

  6. Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996; 272: 263–267.

    Article  CAS  PubMed  Google Scholar 

  7. Ailles LE, Naldini L . HIV-1-derived lentiviral vectors. Curr Top Microbiol Immunol 2002; 261: 31–52.

    CAS  PubMed  Google Scholar 

  8. Levine BL, Humeau LM, Boyer J, MacGregor RR, Rebello T, Lu X et al. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci USA 2006; 103: 17372–17377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Loisel-Meyer S, Felizardo T, Mariotti J, Mossoba ME, Foley JE, Kammerer R et al. Potent induction of B- and T-cell immunity against human carcinoembryonic antigen-expressing tumors in human carcinoembryonic antigen transgenic mice mediated by direct lentivector injection. Mol Cancer Ther 2009; 8: 692–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chapatte L, Colombetti S, Cerottini JC, Levy F . Efficient induction of tumor antigen-specific CD8+ memory T cells by recombinant lentivectors. Cancer Res 2006; 66: 1155–1160.

    Article  CAS  PubMed  Google Scholar 

  11. Chen Y, Emtage P, Zhu Q, Foley R, Muller W, Hitt M et al. Induction of ErbB-2/neu-specific protective and therapeutic antitumor immunity using genetically modified dendritic cells: enhanced efficacy by cotransduction of gene encoding IL-12. Gene Therapy 2001; 8: 316–323.

    Article  CAS  PubMed  Google Scholar 

  12. Chen Z, Huang H, Chang T, Carlsen S, Saxena A, Marr R et al. Enhanced HER-2/neu-specific antitumor immunity by cotransduction of mouse dendritic cells with two genes encoding HER-2/neu and alpha tumor necrosis factor. Cancer Gene Ther 2002; 9: 778–786.

    Article  CAS  PubMed  Google Scholar 

  13. Mossoba ME, Walia JS, Rasaiah VI, Buxhoeveden N, Head R, Ying C et al. Tumor protection following vaccination with low doses of lentivirally transduced DCs expressing the self-antigen erbB2. Mol Ther 2008; 16: 607–617.

    Article  CAS  PubMed  Google Scholar 

  14. Gallo P, Dharmapuri S, Nuzzo M, Maldini D, Iezzi M, Cavallo F et al. Xenogeneic immunization in mice using HER2 DNA delivered by an adenoviral vector. Int J Cancer 2005; 113: 67–77.

    Article  CAS  PubMed  Google Scholar 

  15. Hirschowitz EA, Weaver JD, Hidalgo GE, Doherty DE . Murine dendritic cells infected with adenovirus vectors show signs of activation. Gene Therapy 2000; 7: 1112–1120.

    Article  CAS  PubMed  Google Scholar 

  16. Miller G, Lahrs S, Pillarisetty VG, Shah AB, DeMatteo RP . Adenovirus infection enhances dendritic cell immunostimulatory properties and induces natural killer and T-cell-mediated tumor protection. Cancer Res 2002; 62: 5260–5266.

    CAS  PubMed  Google Scholar 

  17. Morelli AE, Larregina AT, Ganster RW, Zahorchak AF, Plowey JM, Takayama T et al. Recombinant adenovirus induces maturation of dendritic cells via an NF-kappaB-dependent pathway. J Virol 2000; 74: 9617–9628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tillman BW, de Gruijl TD, Luykx-de Bakker SA, Scheper RJ, Pinedo HM, Curiel TJ et al. Maturation of dendritic cells accompanies high-efficiency gene transfer by a CD40-targeted adenoviral vector. J Immunol 1999; 162: 6378–6383.

    CAS  PubMed  Google Scholar 

  19. Zhong L, Granelli-Piperno A, Choi Y, Steinman RM . Recombinant adenovirus is an efficient and non-perturbing genetic vector for human dendritic cells. Eur J Immunol 1999; 29: 964–972.

    Article  CAS  PubMed  Google Scholar 

  20. Wan Y, Bramson J, Carter R, Graham F, Gauldie J . Dendritic cells transduced with an adenoviral vector encoding a model tumor-associated antigen for tumor vaccination. Hum Gene Ther 1997; 8: 1355–1363.

    Article  CAS  PubMed  Google Scholar 

  21. Kamath AT, Henri S, Battye F, Tough DF, Shortman K . Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. Blood 2002; 100: 1734–1741.

    CAS  PubMed  Google Scholar 

  22. Park JM, Terabe M, Sakai Y, Munasinghe J, Forni G, Morris JC et al. Early role of CD4+ Th1 cells and antibodies in HER-2 adenovirus vaccine protection against autochthonous mammary carcinomas. J Immunol 2005; 174: 4228–4236.

    Article  CAS  PubMed  Google Scholar 

  23. Perez-Diez A, Joncker NT, Choi K, Chan WF, Anderson CC, Lantz O et al. CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood 2007; 109: 5346–5354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Quezada SA, Simpson TR, Peggs KS, Merghoub T, Vider J, Fan X et al. Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med 2010; 207: 637–650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pulendran B, Smith JL, Caspary G, Brasel K, Pettit D, Maraskovsky E et al. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc Natl Acad Sci USA 1999; 96: 1036–1041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cerutti A, Qiao X, He B . Plasmacytoid dendritic cells and the regulation of immunoglobulin heavy chain class switching. Immunol Cell Biol 2005; 83: 554–562.

    Article  CAS  PubMed  Google Scholar 

  27. Tang F, Du Q, Liu YJ . Plasmacytoid dendritic cells in antiviral immunity and autoimmunity. Sci China Life Sci 2010; 53: 172–182.

    Article  CAS  PubMed  Google Scholar 

  28. Liu C, Lou Y, Lizee G, Qin H, Liu S, Rabinovich B et al. Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest 2008; 118: 1165–1175.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kim R, Emi M, Tanabe K, Arihiro K . Potential functional role of plasmacytoid dendritic cells in cancer immunity. Immunology 2007; 121: 149–157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lou Y, Liu C, Kim GJ, Liu YJ, Hwu P, Wang G . Plasmacytoid dendritic cells synergize with myeloid dendritic cells in the induction of antigen-specific antitumor immune responses. J Immunol 2007; 178: 1534–1541.

    Article  CAS  PubMed  Google Scholar 

  31. Dai B, Yang L, Yang H, Hu B, Baltimore D, Wang P . HIV-1 Gag-specific immunity induced by a lentivector-based vaccine directed to dendritic cells. Proc Natl Acad Sci USA 2009; 106: 20382–20387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Roth MD, Cheng Q, Harui A, Basak SK, Mitani K, Low TA et al. Helper-dependent adenoviral vectors efficiently express transgenes in human dendritic cells but still stimulate antiviral immune responses. J Immunol 2002; 169: 4651–4656.

    Article  CAS  PubMed  Google Scholar 

  33. Amendola M, Venneri MA, Biffi A, Vigna E, Naldini L . Coordinate dual-gene transgenesis by lentiviral vectors carrying synthetic bidirectional promoters. Nat Biotechnol 2005; 23: 108–116.

    Article  CAS  PubMed  Google Scholar 

  34. Yang TC, Millar J, Groves T, Grinshtein N, Parsons R, Takenaka S et al. The CD8+ T cell population elicited by recombinant adenovirus displays a novel partially exhausted phenotype associated with prolonged antigen presentation that nonetheless provides long-term immunity. J Immunol 2006; 176: 200–210.

    Article  CAS  PubMed  Google Scholar 

  35. Zufferey R, Nagy D, Mandel RJ, Naldini L, Trono D . Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotechnol 1997; 15: 871–875.

    Article  CAS  PubMed  Google Scholar 

  36. Yoshimitsu M, Sato T, Tao K, Walia JS, Rasaiah VI, Sleep GT et al. Bioluminescent imaging of a marking transgene and correction of Fabry mice by neonatal injection of recombinant lentiviral vectors. Proc Natl Acad Sci USA 2004; 101: 16909–16914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Cindy Guo and Kenneth Zhang for their technical assistance in the preparation of plasmids and vectors used in these experiments. We also would like to thank Dr Natalia Pacienza for helping with the processing of samples. This research was funded in part by the Ontario Ministry of Health and Long-Term Care. The views expressed do not necessarily reflect those of the OMOHLTC. Funding was also provided in part by a program project grant from The Terry Fox Foundation Canada to JAM, JLB and DES.

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Authors and Affiliations

  1. Campbell Family Cancer Research Institute and Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

    T C Felizardo & J A Medin

  2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    J C M Wang & J A Medin

  3. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    R A J McGray, C Evelegh & J L Bramson

  4. Department of Medical Oncology, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada

    D E Spaner

  5. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    D E Spaner & J A Medin

  6. Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    D H Fowler

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  1. T C Felizardo
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Correspondence to J A Medin.

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Felizardo, T., Wang, J., McGray, R. et al. Differential immune responses mediated by adenovirus- and lentivirus-transduced DCs in a HER-2/neu overexpressing tumor model. Gene Ther 18, 986–995 (2011). https://doi.org/10.1038/gt.2011.53

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