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:

Mannan-modified adenovirus as a vaccine to induce antitumor immunity

Gene Therapy volume 14, pages 657–663 (2007)Cite this article

Abstract

Tumor vaccine is a useful strategy for cancer therapy. However, priming of the immune system requires the relevant antigen to be presented by antigen-presenting cells (APCs). Here, we employed telomerase reverse transcriptase as a model antigen to explore the feasibility of using mannan-modified adenovirus as a tumor vaccine. We found that tumor immunogene therapy with the vaccine was effective at protective antitumor immunity in mice. The antigen-specific cytotoxic T lymphocytes were found in in vitro cytotoxicity assay. The elevation of the killing activity could be abrogated by anti-CD8 or anti-major histocompatibility complex-I antibodies. Adoptive transfer of purified CD8+ cells, and CD4+ cells to a less extent, was effective at antitumor activity. In vivo antitumor activity could be abrogated by depleting CD4+ T lymphocytes. A possible explanation for the antitumor effects may be the antigen was transfered to APCs in the presence of mannan. These observations provide insights into the design of novel vaccine strategies and might be important for the future application of antigens identified in other 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. Boon TP, van der Bruggen P . Human tumor antigens recognized by T lymphocytes. J Exp Med 1996; 183: 725–729.

    Article  CAS  Google Scholar 

  2. Rosenberg SA . Progress in human tumour immunology and immunotherapy. Nature 2001; 411: 380–384.

    Article  CAS  Google Scholar 

  3. Kikuchi T, Worgall S, Singh R, Moore MA, Crystal RG . Dendritic cells genetically modified to express CD40 ligand and pulsed with antigen can initiate antigen-specific humoral immunity independent of CD4+ T cells. Nat Med 2000; 6: 1154–1159.

    Article  CAS  Google Scholar 

  4. Song W, Kong HL, Carpenter H, Torii H, Granstein R, Rafii S 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  Google Scholar 

  5. Gong J, Chen L, Chen D, Kashiwaba M, Manome Y, Tanaka T et al. Induction of antigen-specific antitumor immunity with adenovirus-transduced dendritic cells. Gene Therapy 1997; 4: 1023–1028.

    Article  CAS  Google Scholar 

  6. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266: 2011–2013.

    Article  CAS  Google Scholar 

  7. Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD et al. hEST, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 1997; 90: 785–795.

    Article  CAS  Google Scholar 

  8. Vonderheide RH . Telomerase as a universal tumor-associated antigen for cancer immunotherapy. Oncogene 2002; 21: 674–679.

    Article  CAS  Google Scholar 

  9. Vonderheide RH, Hahn WC, Schultze JL, Nadler LM . The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes. Immunity 1999; 10: 673–679.

    Article  CAS  Google Scholar 

  10. Heiser A, Maurice MA, Yancey DR, Wu NZ, Dahm P, Pruitt SK et al. Induction of polyclonal prostate cancer-specific CTL using dendritic cells transfected with amplified tumor RNA. J Immunol 2001; 166: 2953–2960.

    Article  CAS  Google Scholar 

  11. Heiser A, Maurice MA, Yancey DR, Coleman DM, Dahm P, Vieweg J . Human dendritic cells transfected with renal tumor RNA stimulated polyclonal T-cell responses against antigens expressed by primary and metastatic tumors. Cancer Res 2001; 61: 3388–3393.

    CAS  PubMed  Google Scholar 

  12. Nair SK, Heiser A, Boczkowski D, Majumdar A, Naoe M, Lebkowski JS et al. Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells. Nat Med 2000; 6: 1011–1017.

    Article  CAS  Google Scholar 

  13. Zhai Y, Yang JC, Kawakami Y, Spiess P, Wadsworth SC, Cardoza LM et al. Antigen-specific tumor vaccines development and characterization of recombinant adenoviruses encoding MART1 or gpl00 for cancer therapy. J Immunol 1996; 156: 700–710.

    CAS  PubMed  Google Scholar 

  14. Toes RE, Hoeben RC, van der Voort EI, Ressing ME, van der Eb AJ, Melief CJ et al. Protective anti-tumor immunity induced by vaccination with recombinant adenoviruses encoding multiple tumor-associated cytotoxic T lymphocyte epitopes in a string-of-beads fashion. Proc Natl Acad Sci USA 1997; 94: 14660–14665.

    Article  CAS  Google Scholar 

  15. 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 

  16. Korokhov N, Mikheeva G, Krendelshchikov A, Belousova N, Simonenko V, Krendelshchikova V et al. Targeting of adenovirus via genetic modification of the viral capsid combined with a protein bridge. J Virol 2003; 77: 12931–12940.

    Article  CAS  Google Scholar 

  17. Wickham TJ, Segal DM, Roelvink PW, Carrion ME, Lizonova A, Lee GM et al. Targeted adenovirus gene transfer to endothelial and smooth muscle cells by using bispecific antibodies. J Virol 1996; 70: 6831–6838.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Belousova N, Korokhov N, Krendelshchikova V, Simonenko V, Mikheeva G, Triozzi PL et al. Genetically targeted adenovirus vector directed to CD40-expressing cells. J Virol 2003; 77: 11367–11377.

    Article  CAS  Google Scholar 

  19. Condaminet B, Peguet-Navarro J, Stahl PD, Dalbiez-Gauthier C, Schmitt D, Berthier-Vergnes O . Human epidermal Langerhans cells express the mannose–fucose binding receptor. Eur J Immunol 1998; 28: 3541–3551.

    Article  CAS  Google Scholar 

  20. Apostolopoulos V, Pietersz GA, Ooveland BE, Sandrin MS, McKenzie IFC . Oxidative/reductive conjugation of mannan to antigen selects for T1 or T2 immune responses. Proc Natl Acad Sci USA 1995; 92: 10128–10132.

    Article  CAS  Google Scholar 

  21. Milone MC, Fitzgerald-Bocarsly P . The Mannose receptor mediates induction of IFN-α in peripheral blood dendritic cells by enveloped RNA and DNA viruses. J Immunol 1998; 161: 2391–2399.

    CAS  PubMed  Google Scholar 

  22. Gross DA, Graff-Dubois S, Opolon P, Cornet S, Alves P, Bennaceur-Griscelli A et al. High vaccination efficiency of low-affinity epitopes in antitumor immunotherapy. J Clin Invest 2004; 113: 425–433.

    Article  CAS  Google Scholar 

  23. Vonderheide RH, Domchek SM, Schultze JL, George DJ, Hoar KM, Chen DY et al. Vaccination of cancer patients against telomerase induces functional antitumor CD8+ T lymphocytes. Clin Cancer Res 2004; 1: 828–839.

    Article  Google Scholar 

  24. Su Z, Dannull J, Yang BK, Dahm P, Coleman D, Yancey D et al. Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol 2005; 174: 3798–3807.

    Article  CAS  Google Scholar 

  25. Carbone FR, Kurts C, Bennett SR, Miller JF, Heath WR . Cross-presentation: a general mechanism for CTL immunity and tolerance. Immunol Today 1998; 19: 368–373.

    Article  CAS  Google Scholar 

  26. Hu HM, Winter H, Urba WJ, Fox BA . Divergent roles for CD4+ T cells in the priming and effector/memory phases of adoptive immunotherapy. J Immunol 2000; 165: 4246–4253.

    Article  CAS  Google Scholar 

  27. Murray JS . How the MHC selects Th1/Th2 immunity. Immunol Today 1998; 19: 157–163.

    Article  CAS  Google Scholar 

  28. Romagnani S . The Th1/Th2 paradigm. Immunol Today 1997; 18: 263–266.

    Article  CAS  Google Scholar 

  29. Chattergoon MA, Kim JJ, Yang JS, Robinson TM, Lee DJ, Dentchev T et al. Targeted antigen delivery to antigen-presenting cells including dendritic cells by engineered Fas-mediated apoptosis. Nat Biotechnol 2000; 18: 974–979.

    Article  CAS  Google Scholar 

  30. Kumamoto T, Huang EK, Paek HJ, Morita A, Matsue H, Valentin RF et al. Induction of tumor-specific protective immunity by in situ Langerhans cell vaccine. Nat Biotechnol 2002; 20: 64–69.

    Article  CAS  Google Scholar 

  31. Merad M, Sugie T, Engleman EG, Fong L . In vivo manipulation of dendritic cells to induce therapeutic immunity. Blood 2002; 99: 1676–1682.

    Article  CAS  Google Scholar 

  32. Watson M, Rudd PM, Bland M, Dwek RA, Axford JS . Sugar printing rheumatic diseases: a potential method for disease differentiation using immunoglobulin G oligosaccharides. Arthritis Rheum 1999; 42: 1682–1690.

    Article  CAS  Google Scholar 

  33. Reitter JN, Means RE, Desrosiers RC . A role for carbohydrates in immune evasion in AIDS. Nat Med 1998; 4: 679–684.

    Article  CAS  Google Scholar 

  34. Prowse KR, Greider CW . Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc Natl Acad Sci USA 1995; 92: 4818–4822.

    Article  CAS  Google Scholar 

  35. Greenberg RA, Allsopp RC, Chin L, Morin GB, De RA . Expression of mouse telomerase reverse transcriptase during development, differentiation and proliferation. Oncogene 1998; 16: 1723–1730.

    Article  CAS  Google Scholar 

  36. Martin-Rivera L, Herrera E, Albar JP, Blasco MA . Expression of mouse telomerase catalytic subunit in embryos and adult tissue. Proc Natl Acad Sci USA 1998; 95: 10471–10476.

    Article  CAS  Google Scholar 

  37. He TC, Zhou S, Costa LT, Yu J, Kinzler KW, Vogelstein B . A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 1998; 95: 2509–2514.

    Article  CAS  Google Scholar 

  38. Hattori Y, Kawakami S, Lu Y, Nakamura K, Yamashita F, Hashida M . Enhanced DNA vaccine potency by mannosylated lipoplex after intraperitoneal administration. J Gene Med 2006; 8: 824–834.

    Article  CAS  Google Scholar 

  39. Hattori Y, Kawakami S, Nakamura K, Yamashita F, Hashida M . Efficient gene transfer into macrophages and dendritic cells by in vivo gene delivery with mannosylated lipoplex via the intraperitoneal route. J Pharmacol Exp Ther 2006; 318: 828–834.

    Article  CAS  Google Scholar 

  40. Lu Y, Wei YQ, Tian L, Zhao X, Yang L, Hu B et al. Immunogene therapy of tumors with vaccine based on xenogeneic epidermal growth factor receptor. J Immunol 2003; 170: 3162–3170.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Key Basic Research Program of China (2004CD518800 and 2001CB510001), Project of National Natural Sciences Foundation of China, National 863 projects.

Author information

Author notes

  1. Z-Y Ding and Y Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, National Key Laboratory of Biotherapy, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, The People's Republic of China

    Z-Y Ding, Y Wu, Y Luo, J-M Su, Q Li, X-W Zhang, J-Y Liu, Q-M He, L Yang, L Tian, X Zhao, H-X Deng, Y-J Wen, J Li, B Kang & Y-Q Wei

Authors
  1. Z-Y Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J-M Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Q Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. X-W Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J-Y Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Q-M He
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. X Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. H-X Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Y-J Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. J Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. B Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Y-Q Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y-Q Wei.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ding, ZY., Wu, Y., Luo, Y. et al. Mannan-modified adenovirus as a vaccine to induce antitumor immunity. Gene Ther 14, 657–663 (2007). https://doi.org/10.1038/sj.gt.3302893

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302893

Keywords

This article is cited by

Search

Advanced search

Quick links