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:

Immunity against breast cancer by TERT DNA vaccine primed with chemokine CCL21

Cancer Gene Therapy volume 14, pages 451–459 (2007)Cite this article

Abstract

Human telomerase reverse transcriptase (TERT) has been considered a potential tumor-associated antigen for active-specific immunotherapy. However, effective specific tumor antigen-specific immunity has been difficult to induce consistently by various TERT vaccine formulations. New adjuvant strategies have been employed, such as utilizing chemokines to attract T cells and antigen-presenting cells. Chemokine adjuvant strategies may enhance tumor antigen-specific immunity induced by vaccines. Therefore, we utilized chemokine ligand 21 (CCL21) as an adjuvant with a xenogeneic TERT DNA vaccine to induce tumor antigen-specific immunity against TERT-expressing breast cancer. The TERT DNA vaccine consisted of a plasmid containing the COOH terminal end of the TERT (cTERT) gene, encapsulated in multilayered liposomes with hemagglutinating virus of Japan coating. We demonstrated that CCL21 treatment before cTERT DNA vaccine, given intramuscularly, induced significantly higher anti-TERT specific cell-mediated immunity compared to cTERT DNA vaccine alone. Effective tumor antigen-specific immunity was shown both in prophylactic and therapeutic regimens against TS/A murine breast cancer. The study demonstrated that CCL21 administration before cTERT DNA vaccination significantly augmented tumor antigen-specific immunity against breast cancer.

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

Similar content being viewed by others

Abbreviations

APCs:

antigen-presenting cells

CCL21:

chemokine ligand 21

CCL21/cTERT vaccine:

cTERT DNA vaccine plus CCL21 24 h before

hTERT:

human TERT

cTERT:

COOH-terminal end of TERT

DC:

dendritic cells

DTH:

delayed-type hypersensitivity

HVJ:

hemagglutinating virus of Japan

TAA:

tumor-associated antigen

TERT:

telomerase reverse transcriptase

TRP2:

tyrosinase-related protein 2

References

  1. Wang RF, Rosenberg SA . Human tumor antigens for cancer vaccine development. Immunol Rev 1999; 170: 85–100.

    Article  CAS  PubMed  Google Scholar 

  2. Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 1997; 277: 955–959.

    Article  CAS  PubMed  Google Scholar 

  3. 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: 2011–2015.

    Article  CAS  PubMed  Google Scholar 

  4. Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A et al. Inhibition of telomerase limits the growth of human cancer cells. Nat Med 1999; 5: 1164–1170.

    Article  CAS  PubMed  Google Scholar 

  5. Liu K, Schoonmaker MM, Levine BL, June CH, Hodes RJ, Weng NP . Constitutive and regulated expression of telomerase reverse transcriptase (hTERT) in human lymphocytes. Proc Natl Acad Sci USA 1999; 96: 5147–5152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Harada K, Kurisu K, Arita K, Sadatomo T, Tahara H, Tahara E et al. Telomerase activity in central nervous system malignant lymphoma. Cancer 1999; 86: 1050–1055.

    Article  CAS  PubMed  Google Scholar 

  7. Bieche I, Nogues C, Paradis V, Olivi M, Bedossa P, Lidereau R et al. Quantitation of hTERT gene expression in sporadic breast tumors with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res 2000; 6: 452–459.

    CAS  PubMed  Google Scholar 

  8. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Minev B, Hipp J, Firat H, Schmidt JD, Langlade-Demoyen P, Zanetti M . Cytotoxic T cell immunity against telomerase reverse transcriptase in humans. Proc Natl Acad Sci USA 2000; 97: 4796–4801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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  PubMed  Google Scholar 

  12. Ayyoub M, Migliaccio M, Guillaume P, Lienard D, Cerottini JC, Romero P et al. Lack of tumor recognition by hTERT peptide 540-548-specific CD8(+) T cells from melanoma patients reveals inefficient antigen processing. Eur J Immunol 2001; 31: 2642–2651.

    Article  CAS  PubMed  Google Scholar 

  13. Vonderheide RH, Schultze JL, Anderson KS, Maecker B, Butler MO, Xia Z et al. Equivalent induction of telomerase-specific cytotoxic T lymphocytes from tumor-bearing patients and healthy individuals. Cancer Res 2001; 61: 8366–8370.

    CAS  PubMed  Google Scholar 

  14. Schroers R, Huang XF, Hammer J, Zhang J, Chen SY . Identification of HLA DR7-restricted epitopes from human telomerase reverse transcriptase recognized by CD4+ T-helper cells. Cancer Res 2002; 62: 2600–2605.

    CAS  PubMed  Google Scholar 

  15. Su Z, Vieweg J, Weizer AZ, Dahm P, Yancey D, Turaga V et al. Enhanced induction of telomerase-specific CD4(+) T cells using dendritic cells transfected with RNA encoding a chimeric gene product. Cancer Res 2002; 62: 5041–5048.

    CAS  PubMed  Google Scholar 

  16. Scardino A, Gross DA, Alves P, Schultze JL, Graff-Dubois S, Faure O et al. HER-2/neu and hTERT cryptic epitopes as novel targets for broad spectrum tumor immunotherapy. J Immunol 2002; 168: 5900–5906.

    Article  CAS  PubMed  Google Scholar 

  17. 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  PubMed  PubMed Central  Google Scholar 

  18. 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; 10: 828–839.

    Article  CAS  PubMed  Google Scholar 

  19. Zou W . Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005; 5: 263–274.

    Article  CAS  PubMed  Google Scholar 

  20. Zhou WZ, Kaneda Y, Huang S, Morishita R, Hoon D . Protective immunization against melanoma by gp100 DNA-HVJ-liposome vaccine. Gene Therapy 1999; 6: 1768–1773.

    Article  CAS  PubMed  Google Scholar 

  21. Tanaka M, Kaneda Y, Fujii S, Yamano T, Hashimoto K, Huang SK et al. Induction of a systemic immune response by a polyvalent melanoma-associated antigen DNA vaccine for prevention and treatment of malignant melanoma. Mol Ther 2002; 5: 291–299.

    Article  CAS  PubMed  Google Scholar 

  22. Yamano T, Kaneda Y, Huang S, Hiramatsu SH, Hoon DS . Enhancement of Immunity by a DNA Melanoma Vaccine against TRP2 with CCL21 as an Adjuvant. Mol Ther 2006; 13: 194–202.

    Article  CAS  PubMed  Google Scholar 

  23. Gold JS, Ferrone CR, Guevara-Patino JA, Hawkins WG, Dyall R, Engelhorn ME et al. A single heteroclitic epitope determines cancer immunity after xenogeneic DNA immunization against a tumor differentiation antigen. J Immunol 2003; 170: 5188–5194.

    Article  CAS  PubMed  Google Scholar 

  24. Homey B, Muller A, Zlotnik A . Chemokines: agents for the immunotherapy of cancer? Nat Rev Immunol 2002; 2: 175–184.

    Article  CAS  PubMed  Google Scholar 

  25. Cyster JG . Chemokines and cell migration in secondary lymphoid organs. Science 1999; 286: 2098–2102.

    Article  CAS  PubMed  Google Scholar 

  26. Nanni P, De Giovanni C, Landuzzi L, Nicoletti G, Frabetti F, Rossi I et al. Therapy of murine mammary carcinoma metastasis with interferon gamma and MHC gene-transduced tumour cells. Br J Cancer 1996; 74: 1564–1569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rodriguez F, Zhang J, Whitton JL . DNA immunization: ubiquitination of a viral protein enhances cytotoxic T-lymphocyte induction and antiviral protection but abrogates antibody induction. J Virol 1997; 71: 8497–8503.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. del Guercio MF, Alexander J, Kubo RT, Arrhenius T, Maewal A, Appella E et al. Potent immunogenic short linear peptide constructs composed of B cell epitopes and Pan DR T helper epitopes (PADRE) for antibody responses in vivo. Vaccine 1997; 15: 441–448.

    Article  CAS  PubMed  Google Scholar 

  29. Ishioka GY, Fikes J, Hermanson G, Livingston B, Crimi C, Qin M et al. Utilization of MHC class I transgenic mice for development of minigene DNA vaccines encoding multiple HLA-restricted CTL epitopes. J Immunol 1999; 162: 3915–3925.

    CAS  PubMed  Google Scholar 

  30. Kolquist KA, Ellisen LW, Counter CM, Meyerson M, Tan LK, Weinberg RA et al. Expression of TERT in early premalignant lesions and a subset of cells in normal tissues. Nat Genet 1998; 19: 182–186.

    Article  CAS  PubMed  Google Scholar 

  31. Kusakabe K, Xin KQ, Katoh H, Sumino K, Hagiwara E, Kawamoto S et al. The timing of GM-CSF expression plasmid administration influences the Th1/Th2 response induced by an HIV-1-specific DNA vaccine. J Immunol 2000; 164: 3102–3111.

    Article  CAS  PubMed  Google Scholar 

  32. Barth A, Hoon DS, Foshag LJ, Nizze JA, Famatiga E, Okun E et al. Polyvalent melanoma cell vaccine induces delayed-type hypersensitivity and in vitro cellular immune response. Cancer Res 1994; 54: 3342–3345.

    CAS  PubMed  Google Scholar 

  33. Soiffer R, Lynch T, Mihm M, Jung K, Rhuda C, Schmollinger JC et al. Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc Natl Acad Sci USA 1998; 95: 13141–13146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xiang R, Mizutani N, Luo Y, Chiodoni C, Zhou H, Mizutani M et al. A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. Cancer Res 2005; 65: 553–561.

    CAS  PubMed  Google Scholar 

  35. Shimizu K, Kuriyama H, Kjaergaard J, Lee W, Tanaka H, Shu S . Comparative analysis of antigen loading strategies of dendritic cells for tumor immunotherapy. J Immunother 2004; 27: 265–272.

    Article  CAS  PubMed  Google Scholar 

  36. Vicari AP, Caux C, Trinchieri G . Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol 2002; 12: 33–42.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the members of Department of Molecular Oncology JWCI and Cedars Sinai Vivarium personnel for their assistance. This work was supported in part by the Komen Breast Center Program and Gonda Laboratory, JWCI.

Author information

Authors and Affiliations

  1. Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA, USA

    T Yamano, S H Hiramatsu, S Huang, A N Tran & D S B Hoon

  2. Division of Gene Therapy Science, Graduate School of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan

    Y Kaneda

  3. Joyce Eisenberg Keefer Breast Center, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA, USA

    A E Giuliano

Authors
  1. T Yamano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Kaneda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S H Hiramatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A N Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A E Giuliano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D S B Hoon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D S B Hoon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamano, T., Kaneda, Y., Hiramatsu, S. et al. Immunity against breast cancer by TERT DNA vaccine primed with chemokine CCL21. Cancer Gene Ther 14, 451–459 (2007). https://doi.org/10.1038/sj.cgt.7701035

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7701035

Keywords

This article is cited by

Search

Advanced search

Quick links