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:

Priming of T cells with aAd-transduced DC followed by expansion with peptide-pulsed DC significantly enhances the induction of tumor-specific CD8+ T cells: implications for an efficient vaccination strategy

Gene Therapy volume 10, pages 243–250 (2003)Cite this article

Abstract

In recent years, vaccination strategies using antigen-presenting cells (APC) have been under investigation. Antigen delivery using genetic immunization through ex vivo transduction of dendritic cells (DC) is supposed to enhance the induction of antitumor responses in humans by activating a broad range of peptide-specific CD8+ T cells. In this study, we compared the potential of adenoviral (Ad)-transduced versus peptide-pulsed DC to induce melanoma-antigen (Ag)-specific T-cell responses in vitro. Whereas gp100-peptide-pulsed DC induced long-lasting specific CD8+ T-cell responses against single peptides, Ad-transduced DC induced broad and strong, specific immunity against various peptides of the gp100-Ag. Surprisingly, several restimulations led to decreasing gp100-specific and in parallel to increasing anti-adenoviral T-cell responses. Nevertheless, those anti-adenoviral T-cell responses provided an ‘adjuvant’ effect by inducing an early release of high amounts of IL-2/IFN-γ, therewith enhancing CTL induction in the initiation phase. Based on these data, we suggest a prime/boost vaccination strategy in melanoma patients – combining the use of Ad-DC and peptide-pulsed DC – to obtain efficient and long-term antitumor T-cell responses.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. van Elsas A et al. Peptide-pulsed dendritic cells induce tumoricidal cytotoxic T lymphocytes from healthy donors against stably HLA-A*0201-binding peptides from the Melan-A/MART-1 self antigen. Eur J Immunol 1996; 26: 1683–1689.

    Article  CAS  PubMed  Google Scholar 

  4. Schuler G, Steinman RM . Dendritic cells as adjuvants for immune-mediated resistance to tumors. J Exp Med 1997; 186: 1183–1187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tüting 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  PubMed  Google Scholar 

  6. Tuting T et al. Dendritic cell-based genetic immunization in mice with a recombinant adenovirus encoding murine TRP2 induces effective anti-melanoma immunity. J Gene Med 1999; 1: 400–406.

    Article  CAS  PubMed  Google Scholar 

  7. Jonuleit H et al. Induction of tumor peptide-specific cytotoxic T cells under serum-free conditions by mature human dendritic cells. Arch Dermatol Res 2000; 292: 325–332.

    Article  CAS  PubMed  Google Scholar 

  8. Nestle FO et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998; 4: 328–332.

    Article  CAS  PubMed  Google Scholar 

  9. Thurner B et al. Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 1999; 190: 1669–1678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jonuleit H et al. A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection. Int J Cancer 2001; 93: 243–251.

    Article  CAS  PubMed  Google Scholar 

  11. Gong J et al. Induction of antigen-specific antitumor immunity with adenovirus-transduced dendritic cells. Gene Ther 1997; 4: 1023–1028.

    Article  CAS  PubMed  Google Scholar 

  12. Song W et al. Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity. J Exp Med 1997; 186: 1247–1256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Specht JM et al. Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases. J Exp Med 1997; 186: 1213–1221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wan Y et al. 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 

  15. Kaplan JM et al. Induction of antitumor immunity with dendritic cells transduced with adenovirus vector-encoding endogenous tumor-associated antigens. J Immunol 1999; 163: 699–707.

    CAS  PubMed  Google Scholar 

  16. Perez-Diez A et al. Generation of CD8+ and CD4+ T-cell response to dendritic cells genetically engineered to express the MART-1/Melan-A gene. Cancer Res 1998; 58: 5305–5309.

    CAS  PubMed  Google Scholar 

  17. Kawakami Y et al. Recognition of multiple epitopes in the human melanoma antigen gp100 by tumor infiltrating T lymphocytes associated with in vivo tumor regression. J Immunol 1995; 154: 3961–3968.

    CAS  PubMed  Google Scholar 

  18. Tsai V et al. Identification of subdominant CTL epitopes of the gp100 melanoma associated tumor antigen by primary in vitro immunization with peptide-pulsed dendritic cells. J Immunol 1997; 158: 1796–1802.

    CAS  PubMed  Google Scholar 

  19. Jonuleit H et al. Efficient transduction of mature CD83+ dendritic cells using recombinant adenovirus suppressed T cell stimulatory capacity. Gene Ther 2000; 7: 249–254.

    Article  CAS  PubMed  Google Scholar 

  20. Ribas A et al. Characterization of antitumor immunization to a defined melanoma antigen using genetically engineered murine dendritic cells. Cancer Gene Ther 1999; 6: 523–536.

    Article  CAS  PubMed  Google Scholar 

  21. Wan Y et al. Enhanced immune response to the melanoma antigen gp100 using recombinant adenovirus-transduced dendritic cells. Cell Immunol 1999 ; 15: 131–138.

    Article  Google Scholar 

  22. Diao J et al. Human PBMC-derived dendritic cells transduced with an adenovirus vector induce cytotoxic T-lymphocyte responses against a vector-encoded antigen in vitro. Gene Ther 1999; 6: 845–853.

    Article  CAS  PubMed  Google Scholar 

  23. Linette GP et al. In vitro priming with adenovirus/gp100 antigen-transduced dendritic cells reveals the epitope specificity of HLA-A*0201-restricted CD8+ T cells in patients with melanoma. J Immunol 2000; 164: 3402–3412.

    Article  CAS  PubMed  Google Scholar 

  24. Zhong L, Granelli-Piperno A, Choi Y, 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 

  25. Song W et al. Persistent, antigen-specific, therapeutic antitumor immunity by dendritic cells genetically modified with an adenoviral vector to express a model tumor antigen. Gene Ther 2000; 7: 2080–2086.

    Article  CAS  PubMed  Google Scholar 

  26. Yang S et al. Dendritic cells infected with a vaccinia vector carrying the human gp100 gene simultaneously present multiple specificities and elicit high-affinity T cells reactive to multiple epitopes and restricted by HLA-A2 and –A3. J Immunol 2000; 164: 4204–4211.

    Article  CAS  PubMed  Google Scholar 

  27. Philip R et al. Dendritic cells loaded with MART-1 peptide or infected with adenoviral construct are functionally equivalent in the induction of tumor-specific cytotoxic T lymphocyte responses in patients with melanoma. J Immunother 2000; 23: 168–176.

    Article  CAS  PubMed  Google Scholar 

  28. Butterfield LH et al. Generation of melanoma-specific cytotoxic T lymphocytes by dendritic cells transduced with a MART-1 adenovirus. J Immunol 1998; 161: 5607–5613.

    CAS  PubMed  Google Scholar 

  29. Rouard H et al. Adenoviral transduction of human clinical grade immature dendritic cells enhances costimulatory molecule expression and T cell stimulatory capacity. J Immunol Methods 2000; 241: 69–81.

    Article  CAS  PubMed  Google Scholar 

  30. Dhodapkar MV et al. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 2001; 193: 233–238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jonuleit H et al. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 2000; 192: 1213–1222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Brossart P . Virus-mediated delivery of antigenic epitopes int dendritic cells as a means to induce CTL. J Immunol 1997; 158: 3270–3276.

    CAS  PubMed  Google Scholar 

  33. Yang Y et al. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci 1994; 9: 4407–4411.

    Article  Google Scholar 

  34. Smith CA, Woodruff LS, Kitchingman GR, Rooney CM . Adenovirus-pulsed dendritic cells stimulate human virus-specific T-cell responses in vitro. J Virol 1996; 70: 6733–6740.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hardy S et al. Construction of adenovirus vectors through Cre-lox recombination. J Virol 1997; 71: 1842–1849.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Walts AE, Said JW, Shintaku IP . Cytodiagnosis of malignant melanoma. Immunoperoxidase staining with HMB-45 antibody as an aid to diagnosis. Am J Clin Pathol 1988; 90: 77–80.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A Kandemir, L Paragnik and P Hölter for excellent technical assistance, R Gärtner for help with the immunostaining of transduced DC and Dr K Steinbrink for critical reading of the manuscript. This work was supported by the German Science Foundation (grant No SFB-432/A6 to AHE).

Author information

Authors and Affiliations

  1. Department of Dermatology, J. Gutenberg-University, Mainz, Germany

    A Tuettenberg, H Jonuleit, T Tüting, J Brück, J Knop & A H Enk

Authors
  1. A Tuettenberg
    View author publications

    Search author on:PubMed Google Scholar

  2. H Jonuleit
    View author publications

    Search author on:PubMed Google Scholar

  3. T Tüting
    View author publications

    Search author on:PubMed Google Scholar

  4. J Brück
    View author publications

    Search author on:PubMed Google Scholar

  5. J Knop
    View author publications

    Search author on:PubMed Google Scholar

  6. A H Enk
    View author publications

    Search author on:PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tuettenberg, A., Jonuleit, H., Tüting, T. et al. Priming of T cells with aAd-transduced DC followed by expansion with peptide-pulsed DC significantly enhances the induction of tumor-specific CD8+ T cells: implications for an efficient vaccination strategy. Gene Ther 10, 243–250 (2003). https://doi.org/10.1038/sj.gt.3301880

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.gt.3301880

Keywords

This article is cited by

Search

Advanced search

Quick links