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.

  • Original Article
  • Published:

Engineering of highly immunogenic long-lived DC vaccines by antiapoptotic protein gene transfer to enhance cancer vaccine potency

Gene Therapy volume 15, pages 1321–1329 (2008)Cite this article

Abstract

Dendritic cells (DCs) have a critical role in the induction of antigen-specific immune responses, transporting antigens from peripheral tissue to regional lymph nodes where they interact with antigen-specific T lymphocytes. Recent studies revealed that the efficacy of the T cell-dependent immune response depends on the lifespan of the antigen-presenting DCs in the lymph nodes. Here, we succeeded in engineering long-lived antigen-presenting DCs via Bcl-xL-derived hyperactive mutant antiapoptotic protein (Bcl-xFNK) gene transfer. In a B16BL6 melanoma model, these long-lived DCs exerted potent antitumor immunity that depended mainly on antigen-specific cytotoxic T lymphocytes. Furthermore, in vivo longevity of the long-lived DC vaccine led to antigen-specific activation of interferon-γ-producing CD4+ and CD8+ T cells. Thus, the long-lived DC vaccine strategy is highly useful for constructing DC vaccines, as well as other cell-based medicines, such as stem cell therapy.

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

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Randolph GJ, Angeli V, Swartz MA . Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol 2005; 5: 617–628.

    Article  CAS  PubMed  Google Scholar 

  3. Schuler G, Schuler-Thurner B, Steinman RM . The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 2003; 15: 138–147.

    Article  CAS  PubMed  Google Scholar 

  4. Ridgway D . The first 1000 dendritic cell vaccinees. Cancer Invest 2003; 21: 873–886.

    Article  PubMed  Google Scholar 

  5. Hermans IF, Ritchie DS, Yang J, Roberts JM, Ronchese F . CD8+ T cell-dependent elimination of dendritic cells in vivo limits the induction of antitumor immunity. J Immunol 2000; 164: 3095–3101.

    Article  CAS  PubMed  Google Scholar 

  6. Liu K, Iyoda T, Saternus M, Kimura Y, Inaba K, Steinman RM . Immune tolerance after delivery of dying cells to dendritic cells in situ. J Exp Med 2002; 196: 1091–1097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nestle FO . A new lease on life for dendritic cell vaccines? Nat Biotechnol 2006; 24: 1483–1484.

    Article  CAS  PubMed  Google Scholar 

  8. Chen M, Huang L, Shabier Z, Wang J . Regulation of the lifespan in dendritic cell subsets. Mol Immunol 2007; 44: 2558–2565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Park Y, Lee SW, Sung YC . Cutting Edge: CpG DNA inhibits dendritic cell apoptosis by up-regulating cellular inhibitor of apoptosis proteins through the phosphatidylinositide-3′-OH kinase pathway. J Immunol 2002; 168: 5–8.

    Article  CAS  PubMed  Google Scholar 

  10. Josien R, Li HL, Ingulli E, Sarma S, Wong BR, Vologodskaia M et al. TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J Exp Med 2000; 191: 495–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Miga AJ, Masters SR, Durell BG, Gonzalez M, Jenkins MK, Maliszewski C et al. Dendritic cell longevity and T cell persistence is controlled by CD154-CD40 interactions. Eur J Immunol 2001; 31: 959–965.

    Article  CAS  PubMed  Google Scholar 

  12. Nopora A, Brocker T . Bcl-2 controls dendritic cell longevity in vivo. J Immunol 2002; 169: 3006–3014.

    Article  CAS  PubMed  Google Scholar 

  13. Hon H, Rucker III EB, Hennighausen L, Jacob J . bcl-xL is critical for dendritic cell survival in vivo. J Immunol 2004; 173: 4425–4432.

    Article  CAS  PubMed  Google Scholar 

  14. Hou WS, Van Parijs L . A Bcl-2-dependent molecular timer regulates the lifespan and immunogenicity of dendritic cells. Nat Immunol 2004; 5: 583–589.

    Article  CAS  PubMed  Google Scholar 

  15. Dmitriev I, Krasnykh V, Miller CR, Wang M, Kashentseva E, Mikheeva G et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism. J Virol 1998; 72: 9706–9713.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Okada N, Tsukada Y, Nakagawa S, Mizuguchi H, Mori K, Saito T et al. Efficient gene delivery into dendritic cells by fiber-mutant adenovirus vectors. Biochem Biophys Res Commun 2001; 282: 173–179.

    Article  CAS  PubMed  Google Scholar 

  17. Okada N, Masunaga Y, Okada Y, Iiyama S, Mori N, Tsuda T et al. Gene transduction efficiency and maturation status in mouse bone marrow-derived dendritic cells infected with conventional or RGD fiber-mutant adenovirus vectors. Cancer Gene Ther 2003; 10: 421–431.

    Article  CAS  PubMed  Google Scholar 

  18. Okada N, Saito T, Masunaga Y, Tsukada Y, Nakagawa S, Mizuguchi H et al. Efficient antigen gene transduction using Arg-Gly-Asp fiber-mutant adenovirus vectors can potentiate antitumor vaccine efficacy and maturation of murine dendritic cells. Cancer Res 2001; 61: 7913–7919.

    CAS  PubMed  Google Scholar 

  19. Asoh S, Ohsawa I, Mori T, Katsura K, Hiraide T, Katayama Y et al. Protection against ischemic brain injury by protein therapeutics. Proc Natl Acad Sci USA 2002; 99: 17107–17112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ashkenazi A, Dixit VM . Death receptors: signaling and modulation. Science 1998; 281: 1305–1308.

    Article  CAS  PubMed  Google Scholar 

  21. Green DR, Reed JC . Mitochondria and apoptosis. Science 1998; 281: 1309–1312.

    Article  CAS  PubMed  Google Scholar 

  22. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 2000; 403: 98–103.

    Article  CAS  PubMed  Google Scholar 

  23. Ingulli E, Mondino A, Khoruts A, Jenkins MK . In vivo detection of dendritic cell antigen presentation to CD4(+) T cells. J Exp Med 1997; 185: 2133–2141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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 

  25. Park D, Lapteva N, Seethammagari M, Slawin KM, Spencer DM . An essential role for Akt1 in dendritic cell function and tumor immunotherapy. Nat Biotechnol 2006; 24: 1581–1590.

    Article  CAS  PubMed  Google Scholar 

  26. Mizuguchi H, Funakoshi N, Hosono T, Sakurai F, Kawabata K, Yamaguchi T et al. Rapid construction of small interfering RNA-expressing adenoviral vectors on the basis of direct cloning of short hairpin RNA-coding DNAs. Hum Gene Ther 2007; 18: 74–80.

    Article  CAS  PubMed  Google Scholar 

  27. Kang TH, Lee JH, Noh KH, Han HD, Shin BC, Choi EY et al. Enhancing dendritic cell vaccine potency by combining a BAK/BAX siRNA-mediated antiapoptotic strategy to prolong dendritic cell life with an intracellular strategy to target antigen to lysosomal compartments. Int J Cancer 2007; 120: 1696–1703.

    Article  CAS  PubMed  Google Scholar 

  28. Kim TW, Hung CF, Boyd D, Juang J, He L, Kim JW 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 

  29. Kim JH, Chen J, Majumder N, Lin H, Falo Jr LD, You Z . ‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity. Gene Therapy 2005; 12: 1517–1525.

    Article  CAS  PubMed  Google Scholar 

  30. Reinhard G, Marten A, Kiske SM, Feil F, Bieber T, Schmidt-Wolf IG . Generation of dendritic cell-based vaccines for cancer therapy. Br J Cancer 2002; 86: 1529–1533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Okada N, Masunaga Y, Okada Y, Mizuguchi H, Iiyama S, Mori N et al. Dendritic cells transduced with gp100 gene by RGD fiber-mutant adenovirus vectors are highly efficacious in generating anti-B16BL6 melanoma immunity in mice. Gene Therapy 2003; 10: 1891–1902.

    Article  CAS  PubMed  Google Scholar 

  32. Okada N, Mori N, Koretomo R, Okada Y, Nakayama T, Yoshie O et al. Augmentation of the migratory ability of DC-based vaccine into regional lymph nodes by efficient CCR7 gene transduction. Gene Therapy 2005; 12: 129–139.

    Article  CAS  PubMed  Google Scholar 

  33. Harding CV, Song R . Phagocytic processing of exogenous particulate antigens by macrophages for presentation by class I MHC molecules. J Immunol 1994; 153: 4925–4933.

    CAS  PubMed  Google Scholar 

  34. Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 1999; 223: 77–92.

    Article  CAS  PubMed  Google Scholar 

  35. Mizuguchi H, Kay MA . Efficient construction of a recombinant adenovirus vector by an improved in vitro ligation method. Hum Gene Ther 1998; 9: 2577–2583.

    Article  CAS  PubMed  Google Scholar 

  36. Mizuguchi H, Koizumi N, Hosono T, Utoguchi N, Watanabe Y, Kay MA et al. A simplified system for constructing recombinant adenoviral vectors containing heterologous peptides in the HI loop of their fiber knob. Gene Therapy 2001; 8: 730–735.

    Article  CAS  PubMed  Google Scholar 

  37. Mizuguchi H, Kay MA . A simple method for constructing E1- and E1/E4-deleted recombinant adenoviral vectors. Hum Gene Ther 1999; 10: 2013–2017.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Sadamitsu Asoh and Dr Shigeo Ohta (Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kanagawa, Japan) for providing pEF1BOS-Bcl-xFNK and pEF1BOS-Bcl-xL; to Dr Hirofumi Hamada (Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan) for providing pAx1-CA h-gp100; to Dr Masaru Okabe (Genome Information Research Center, Osaka University, Suita, Japan) for providing the C57BL/6 TgN(act-EGFP)OsbC14-Y01-FM131 mice; to Dr Clifford V Harding (Department of Pathology, Case Western Reserve University, Cleveland, OH, USA) for providing the CD8-OVA1.3 cells; and to Dr Hiroshi Yamamoto (Department of Immunology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan) for providing GK1.5 ascites and 53-6.72 ascites. This study was supported in part by grants from the Ministry of Health, Labor, and Welfare of Japan (S Nakagawa); Scientific Research in Priority Areas (17016043: S Nakagawa), Exploratory Research (17659047: S Nakagawa), and a Grant-in-Aid for Young Scientists (A) (18689007: N Okada) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Health Science Research Including Drug Innovation (KH53313: N Okada) from the Japan Health Sciences Foundation.

Author information

Author notes

  1. T Yoshikawa

    Present address: 3Current address: Center for Advanced Research and Education in Drug Discovery and Development, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.,

Authors and Affiliations

  1. Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan

    T Yoshikawa, T Niwa, N Okada & S Nakagawa

  2. Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka, Japan

    H Mizuguchi

Authors
  1. T Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Niwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Mizuguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to N Okada or S Nakagawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoshikawa, T., Niwa, T., Mizuguchi, H. et al. Engineering of highly immunogenic long-lived DC vaccines by antiapoptotic protein gene transfer to enhance cancer vaccine potency. Gene Ther 15, 1321–1329 (2008). https://doi.org/10.1038/gt.2008.85

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2008.85

Keywords

This article is cited by

Search

Advanced search

Quick links