Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Cancer immunotherapy using a DNA vaccine encoding a single-chain trimer of MHC class I linked to an HPV-16 E6 immunodominant CTL epitope

Gene Therapy volume 12, pages 1180–1186 (2005)Cite this article

Abstract

The potency of DNA vaccines may be affected by the efficiency of intracellular processing and MHC class I presentation of encoded antigens. Since a single-chain trimer (SCT) composed of peptide, β2-microglobulin (β2m), and MHC class I heavy chain has been shown to bypass antigen processing and lead to stable presentation of peptides, we investigated the efficacy of a DNA vaccine encoding a SCT composed of an immunodominant CTL epitope of human papillomavirus type 16 (HPV-16) E6 antigen, β2m, and H-2Kb MHC class I heavy chain (pIRES-E6-β2m-Kb). Transfection of 293 cells with pIRES-E6-β2m-Kb can bypass antigen processing and lead to stable presentation of E6 peptide. Furthermore, C57BL/6 mice vaccinated with pIRES-E6-β2m-Kb exhibited significantly increased E6 peptide-specific CD8+ T-cell immune responses compared to mice vaccinated with DNA encoding wild-type E6. Most importantly, 100% of mice vaccinated with pIRES-E6-β2m-Kb DNA were protected against a lethal challenge of E6-expressing TC-1 tumor cells. In contrast, all mice vaccinated with wild-type E6 DNA or control plasmid DNA grew tumors. Our data indicate that a DNA vaccine encoding a SCT can lead to stable enhanced MHC class I presentation of encoded antigenic peptide and may be useful for improving DNA vaccine potency to control tumors or infectious diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Boyd D, Hung CF, Wu TC . DNA vaccines for cancer. IDrugs 2003; 6: 1155–1164.

    CAS  PubMed  Google Scholar 

  2. Donnelly JJ, Ulmer JB, Shiver JW, Liu MA . DNA vaccines. Annu Rev Immunol 1997; 15: 617–648.

    Article  CAS  PubMed  Google Scholar 

  3. Gurunathan S, Klinman DM, Seder RA . DNA vaccines: immunology, application, and optimization*. Annu Rev Immunol 2000; 18: 927–974.

    Article  CAS  PubMed  Google Scholar 

  4. Hung CF, Wu TC . Improving DNA vaccine potency via modification of professional antigen presenting cells. Curr Opin Mol Ther 2003; 5: 20–24.

    CAS  PubMed  Google Scholar 

  5. Pamer E, Cresswell P . Mechanisms of MHC class I-restricted antigen processing. Annu Rev Immunol 1998; 16: 323–358.

    Article  CAS  PubMed  Google Scholar 

  6. Mottez E et al. Cells expressing a major histocompatibility complex class I molecule with a single covalently bound peptide are highly immunogenic. J Exp Med 1995; 181: 493–502.

    Article  CAS  PubMed  Google Scholar 

  7. Uger RA, Barber BH . Creating CTL targets with epitope-linked beta 2-microglobulin constructs. J Immunol 1998; 160: 1598–1605.

    CAS  PubMed  Google Scholar 

  8. Yu YY et al. Cutting edge: single-chain trimers of MHC class I molecules form stable structures that potently stimulate antigen-specific T cells and B cells. J Immunol 2002; 168: 3145–3149.

    Article  CAS  PubMed  Google Scholar 

  9. Lin K-Y et al. Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res 1996; 56: 21–26.

    CAS  PubMed  Google Scholar 

  10. zur Hausen H . Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002; 2: 342–350.

    Article  CAS  PubMed  Google Scholar 

  11. Peng S et al. Development of a DNA vaccine targeting HPV-16 oncogenic protein E6. J. Virol. 2004; 78: 8468–8476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ji H et al. Antigen-specific immunotherapy for murine lung metastatic tumors expressing human papillomavirus type 16 E7 oncoprotein. Int J Cancer 1998; 78: 41–45.

    Article  CAS  PubMed  Google Scholar 

  13. Porgador A et al. Predominant role for directly transfected dendritic cells in antigen presentation to CD8+ T cells after gene gun immunization. J Exp Med 1998; 188: 1075–1082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kim TW et al. Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins. J Clin Invest 2003; 112: 109–117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kim TW et al. Enhancing DNA vaccine potency by combining a strategy to prolong dendritic cell life with intracellular targeting strategies. J Immunol 2003; 171: 2970–2976.

    Article  CAS  PubMed  Google Scholar 

  16. Chung DH et al. NK and CTL recognition of a single chain H-2Dd molecule: distinct sites of H-2Dd interact with NK and TCR. J Immunol 1999; 163: 3699–3708.

    CAS  PubMed  Google Scholar 

  17. Lee L et al. Functional cell surface expression by a recombinant single-chain class I major histocompatibility complex molecule with a cis-active beta 2-microglobulin domain. Eur J Immunol 1994; 24: 2633–2639.

    Article  CAS  PubMed  Google Scholar 

  18. Lone YC et al. In vitro induction of specific cytotoxic T lymphocytes using recombinant single-chain MHC class I/peptide complexes. J Immunother 1998; 21: 283–294.

    Article  CAS  PubMed  Google Scholar 

  19. Lybarger L et al. Enhanced immune presentation of a single-chain major histocompatibility complex class I molecule engineered to optimize linkage of a C-terminally extended peptide. J Biol Chem 2003; 278: 27105–27111.

    Article  CAS  PubMed  Google Scholar 

  20. Anjuere F, Horvath C, Cerottini JC, Luescher IF . Induction of CTL in vivo by major histocompatibility complex class I–peptide complexes covalently associated on the cell surface. Eur J Immunol 1995; 25: 1535–1540.

    Article  CAS  PubMed  Google Scholar 

  21. Greten TF et al. Peptide–beta2-microglobulin–MHC fusion molecules bind antigen-specific T cells and can be used for multivalent MHC–Ig complexes. J Immunol Methods 2002; 271: 125–135.

    Article  CAS  PubMed  Google Scholar 

  22. Slansky JE et al. Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC–peptide–TCR complex. Immunity 2000; 13: 529–538.

    Article  CAS  PubMed  Google Scholar 

  23. Chen C-H et al. Enhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene. Cancer Res 2000; 60: 1035–1042.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Richard Roden for helpful discussions. We would also like to thank Drs Ralph Hruban and Ken-Yu Lin for critical review of this paper. This work was supported by grants from the National Institute of Allergy and Infectious Disease, the National Cancer Institute, and the American Cancer Society.

Author information

Author notes

  1. C-H Huang and S Peng: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    C-H Huang, S Peng, L He, Y-C Tsai, D A K Boyd & C-F Hung

  2. Departments of Genetics and Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA

    T H Hansen

  3. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu & C-F Hung

  4. Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

  5. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

Authors
  1. C-H Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y-C Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D A K Boyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T H Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T-C Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C-F Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, CH., Peng, S., He, L. et al. Cancer immunotherapy using a DNA vaccine encoding a single-chain trimer of MHC class I linked to an HPV-16 E6 immunodominant CTL epitope. Gene Ther 12, 1180–1186 (2005). https://doi.org/10.1038/sj.gt.3302519

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302519

Keywords

This article is cited by

Search

Advanced search

Quick links