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.

  • Acquired Diseases
  • Published:

Intramuscular administration of E7-transfected dendritic cells generates the most potent E7-specific anti-tumor immunity

Gene Therapy volume 7, pages 726–733 (2000)Cite this article

Abstract

Dendritic cells (DCs) are highly efficient antigen-presenting cells capable of priming both cytotoxic and helper T cells in vivo. Recent studies have demonstrated the potential use of DCs that are modified to carry tumor-specific antigens in cancer vaccines. However, the optimal administration route of DC-based vaccines to generate the greatest anti-tumor effect remains to be determined. This study is aimed at comparing the levels of immune responses and anti-tumor effect generated through different administration routes of DC-based vaccination. We chose the E7 gene product of human papillomavirus (HPV) as the model antigen and generated a stable DC line (designated as DC-E7) that constitutively expresses the E7 gene. Among the three different routes of DC-E7 vaccine administration in a murine model, we found that intramuscular administration generated the greatest anti-tumor immunity compared with subcutaneous and intravenous routes of administration. Furthermore, intramuscular administration of DC-E7 elicited the highest levels of E7-specific antibody and greatest numbers of E7-specific CD4+ T helper and CD8+ T cell precursors. Our results indicate that the potency of DC-based vaccines depends on the specific route of administration and that intramuscular administration of E7-transfected DCs generates the most potent E7-specific anti-tumor immunity.

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
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Steinman RM . The dendritic cell system and its role in immunogenicity (review) Annu Rev Immunol 1991 9: 271–296

    Article  CAS  PubMed  Google Scholar 

  2. Cella M, Sallusto F, Lanzavecchia A . Origin, maturation and antigen presenting function of dendritic cells (review) Curr Opin Immunol 1997 9: 10–16

    Article  CAS  PubMed  Google Scholar 

  3. Hart DN . Dendritic cells: unique leukocyte populations which control the primary immune response Blood 1997 90: 3245–3287

    CAS  PubMed  Google Scholar 

  4. Romani N et al. Presentation of exogenous protein antigens by dendritic cells to T cell clones. Intact protein is presented best by immature, epidermal Langerhans cells J Exp Med 1989 169: 1169–1178

    Article  CAS  PubMed  Google Scholar 

  5. van Kooten C, Banchereau J . Functional role of CD40 and its ligand (review) Int Arch Allerg Immunol 1997 113: 393–399

    Article  CAS  Google Scholar 

  6. Pierre P et al. Developmental regulation of MHC class II transport in mouse dendritic cells Nature 1997 388: 787–792

    Article  CAS  PubMed  Google Scholar 

  7. Cella M et al. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells Nature 1997 388: 782–787

    Article  CAS  PubMed  Google Scholar 

  8. Austyn JM . New insights into the mobilization and phagocytic activity of dendritic cells J Exp Med 1996 183: 1287–1292

    Article  CAS  PubMed  Google Scholar 

  9. Mayordomo JI et al. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity Nature Med 1995 1: 1297–1302

    Article  CAS  PubMed  Google Scholar 

  10. Ossevoort MA et al. Dendritic cells as carriers for a cytotoxic T-lymphocyte epitope-based peptide vaccine in protection against a human papillomavirus type 16-induced tumor J Immunother Emph Tumor Immunol 1995 18: 86–94

    Article  CAS  Google Scholar 

  11. Mayordomo JI et al. Bone marrow-derived dendritic cells serve as potent adjuvants for peptide-based antitumor vaccines (review) Stem Cells 1997 15: 94–103

    Article  CAS  PubMed  Google Scholar 

  12. Rouse RJ et al. Induction in vitro of primary cytotoxic T-lymphocyte responses with DNA encoding herpes simplex virus proteins J Virol 1994 68: 5685–5689

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Tuting T, DeLeo AB, Lotze MT, Storkus WJ . Genetically modified bone marrow-derived dendritic cells expressing tumor-associated viral or ‘self’ antigens induce antitumor immunity in vivo Eur J Immunol 1997 27: 2702–2707

    Article  CAS  PubMed  Google Scholar 

  14. Arthur JF et al. A comparison of gene transfer methods in human dendritic cells Cancer Gene Ther 1997 4: 17–25

    CAS  PubMed  Google Scholar 

  15. Dietz AB, Vuk-Pavlovic S . High efficiency adenovirus-mediated gene transfer to human dendritic cells Blood 1998 91: 392–398

    CAS  PubMed  Google Scholar 

  16. Dranoff G et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte–macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity Proc Natl Acad Sci USA 1993 90: 3539–3543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nair SK, Snyder D, Rouse BT, Gilboa E . Regression of tumors in mice vaccinated with professional antigen-presenting cells pulsed with tumor extracts Int J Cancer 1997 70: 706–715

    Article  CAS  PubMed  Google Scholar 

  18. Yang S, Darrow TL, Vervaert CE, Seigler HF . Immunotherapeutic potential of tumor antigen-pulsed and unpulsed dendritic cells generated from murine bone marrow Cell Immunol 1997 179: 84–95

    Article  CAS  PubMed  Google Scholar 

  19. Ashley DM et al. Bone marrow-generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors J Exp Med 1997 186: 1177–1182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shen Z, Reznikoff G, Dranoff G, Rock KL . Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules J Immunol 1997 158: 2723–2730

    CAS  PubMed  Google Scholar 

  21. Tatsuka M, Orita S, Yagi T, Kakunaga T . An improved method of electroporation for introducing biologically active foreign genes into cultured mammalian cells Exp Cell Res 1988 178: 154–162

    Article  CAS  PubMed  Google Scholar 

  22. Lin KY 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 

  23. Feltkamp MC et al. Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells Eur J Immunol 1993 23: 2242–2249

    Article  CAS  PubMed  Google Scholar 

  24. Tindle RW, Fernando GJ, Sterling JC, Frazer IH . A ‘public’ T-helper epitope of the E7 transforming protein of human papillomavirus 16 provides cognate help for several E7 B-cell epitopes from cervical cancer-associated human papillomavirus genotypes Proc Natl Acad Sci USA 1991 88: 5887–5891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Morse MA et al. Migration of human dendritic cells after injection in patients with metastatic malignancies Cancer Res 1999 59: 56–58

    CAS  PubMed  Google Scholar 

  26. Eggert AA et al. Biodistribution and vaccine efficiency of murine dendritic cells are dependent on the route of administration Cancer Res 1999 59: 3340–3345

    CAS  PubMed  Google Scholar 

  27. Banchereau J, Steinman RM . Dendritic cells and the control of immunity Nature 1998 392: 245–252

    Article  CAS  PubMed  Google Scholar 

  28. Germain RN . MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation (review) Cell 1994 76: 287–299

    Article  CAS  PubMed  Google Scholar 

  29. Inaba K et al. Tissue distribution of the DEC-205 protein that is detected by the monoclonal antibody NLDC-145. 1: Expression on dendritic cells and other subsets of mouse leukocytes Cell Immunol 1995 163: 148–156

    Article  CAS  PubMed  Google Scholar 

  30. Ji H et al. Targeting HPV-16 E7 to the endosomal lysosomal compartment enhances the antitumor immunity of DNA vaccines against murine HPV-16 E7-expressing tumors Hum Gene Ther 1999 10: 2727–2740

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The immortalized dendritic cell line is a kind gift from Dr Kenneth L Rock. We thank Yan-Qin Yang and Hai-Yan Chen for their excellent technical assistance. We thank Lee Wu for her assistance in statistical analysis. This work was supported by NIH 5 PO1 34582–01, U19 CA72108–02, RO1 CA72631–01, Cancer Research Institute, the Richard W TeLinde fund and the Alexander and Margaret Stewart Trust grant.

Author information

Authors and Affiliations

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

    T-L Wang, M Ling, I-M Shih, T Pham, R J Kurman, D M Pardoll & T-C Wu

  2. Department of Oncology, The Johns Hopkins Medical Institution, Baltimore, MD, USA

    S I Pai, Z Lu, D M Pardoll & T-C Wu

  3. Department of Gynecology and Obstetrics, The Johns Hopkins Medical Institution, Baltimore, MD, USA

    R J Kurman & T-C Wu

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

    T-C Wu

Authors
  1. T-L Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I-M Shih
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Pham
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S I Pai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Z Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R J Kurman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D M Pardoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T-C Wu
    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

Wang, TL., Ling, M., Shih, IM. et al. Intramuscular administration of E7-transfected dendritic cells generates the most potent E7-specific anti-tumor immunity. Gene Ther 7, 726–733 (2000). https://doi.org/10.1038/sj.gt.3301160

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301160

Keywords

This article is cited by

Search

Advanced search

Quick links