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:

New strategy for the identification of squamous carcinoma antigens that induce therapeutic immune responses in tumor-bearing mice

Cancer Gene Therapy volume 14, pages 389–398 (2007)Cite this article

Abstract

This study describes a new strategy for the identification of squamous carcinoma antigens tumor-associated antigens (TAA). The antigens were discovered by comparing microarrays of squamous carcinoma vaccines highly enriched for immunotherapeutic cells with non-enriched vaccines. The vaccines were prepared by transferring sheared genomic DNA fragments (25 kb) from KLN205 cells, a squamous carcinoma cell line (DBA/2 mouse origin (H-2d) into LM fibroblasts (C3H/He origin, H-2k). The transferred tumor DNA segments integrate spontaneously into the genome of the recipient cells, replicate as the cells divide and are expressed. As only a small proportion of the transfected cell population was expected to have incorporated DNA segments that included genes specifying TAA (the vast majority specify normal cellular constituents), a novel strategy was employed to enrich the vaccine for TAA-positive cells. Microarrays were used to compare genes expressed by enriched and non-enriched vaccines. Seventy-five genes were overexpressed in cells from the enriched vaccine. One, the gene for Cytochrome P450 (family 2, subfamily e, polypeptide 1) (Cyp2e1), was overexpressed in the enriched but not the non-enriched vaccine. A vaccine for squamous carcinoma was prepared by transfer of a 357 bp fragment of the gene for Cyp2e1 into the fibroblast cell line. Robust immunity, sufficient to result in indefinite survival, was induced in tumor-bearing mice immunized with cells transfected with this gene fragment.

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

References

  1. American Cancer Society: Cancer Facts and Figures 2006.

  2. Herold-Mende C, Karcher J, Dyckhoff G, Schirrmacher V . Antitumor immunization of head and neck squamous cell carcinoma patients with a virus-modified autologous tumor cell vaccine. Adv Otorhinolaryngol 2005; 62: 173–183.

    Google Scholar 

  3. Hoffmann TK, Bier H, Donnenberg AD, Whiteside TL, De Leo AB . p53 as an immunotherapeutic target in head and neck cancer. Adv Otorhinolaryngol 2005; 62: 151–160.

    CAS  PubMed  Google Scholar 

  4. Cheever MA, Disis ML, Bernhard H, Gralow JR, Hand SL, Huseby ES et al. Immunity to oncogenic proteins. Immunol Rev 1995; 145: 33–59.

    Article  CAS  Google Scholar 

  5. Disis ML, Cheever MA . Oncogenic proteins as tumor antigens. Curr Opn Immunol 1996; 8: 637–642.

    Article  CAS  Google Scholar 

  6. Ferris RL . Progress in head and neck cancer immunotherapy: can tolerance and immune suppression be reversed? ORL J Otorhinolaryngol Relat Spec 2004; 66: 332–640.

    Article  Google Scholar 

  7. Yoshitake Y, Nakatsura T, Monji M . Proliferation potential-related protein, an ideal esophageal cancer antigen for immunotherapy, identified using complementary DNA microarray analysis. Clin Cancer Res 2004; 10: 6437–6448.

    Article  CAS  Google Scholar 

  8. Russo G, Zegar C, Giordano A . Advantages and limitations of microarray technology in human cancer. Oncogene 2003; 22: 6497–6507.

    Article  CAS  Google Scholar 

  9. Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topolian SL et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 1998; 4: 321–327.

    Article  CAS  Google Scholar 

  10. Jaeger E, Bernhard H, Romero P, Ringhoffer M, Arand M, Karbach J et al. Generation of cytotoxic T-cell responses with synthetic melanoma-associated peptides in vivo, implications for tumor vaccines with melanoma-associated antigens. Int J Cancer 1996; 66: 162–169.

    Article  CAS  Google Scholar 

  11. Mu LJ, Kyte JA, Kvalheim G, Aamdal S, Dueland S, Hauser M et al. Immunotherapy with allotumour mRNA-transfected dendritic cells in androgen-resistant prostate cancer patients. Br J Cancer 2005; 93: 749–756.

    Article  CAS  Google Scholar 

  12. Steitz J, Britten CM, Wolfel T, Tuting T . Effective induction of anti-melanoma immunity following genetic vaccination with synthetic mRNA coding for the fusion protein EGFP.TRP2. Cancer Immunol Immunother 2006; 55: 246–253.

    Article  CAS  Google Scholar 

  13. Lee WC, Wang HC, Hung CF, Huang PF, Lia CR, Chen MF . Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother 2005; 28: 496–504.

    Article  Google Scholar 

  14. Hus I, Rolinski J, Tabarkiewicz J, Wojas K, Bojarska-Junak A, Greiner J et al. Allogeneic dendritic cells pulsed with tumor lysates or apoptotic bodies as immunotherapy for patients with early-stage B-cell chronic lymphocytic leukemia. Leukemia 2005; 19: 1621–1627.

    Article  CAS  Google Scholar 

  15. Hayashi T, Nakao K, Nagayama Y, Saitoh O, Ichikawa T, Ishikawa H et al. Vaccination with dendritic cells pulsed with apoptotic cells elicits effective antitumor immunity in murine hepatoma models. Int J Oncol 2005; 26: 1313–1319.

    CAS  PubMed  Google Scholar 

  16. Cuadros C, Dominguez AL, Lollini PL, Croft M, Mittler RS, Borgstrom P et al. Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice. Int J Cancer 2005; 116: 934–943.

    Article  CAS  Google Scholar 

  17. Dalgleish AG, Whelan MA . Cancer vaccines as a therapeutic modality: the long trek. Cancer Immunol Immunother 2006; 55: 1025–1032.

    Article  CAS  Google Scholar 

  18. Boon T, Cerrottini JC, Van den Eynde B, van er Bruggen P, Van Pel A . Tumor antigens recognized by T lymphocytes. Annu Rev Immunol 1994; 12: 337–365.

    Article  CAS  Google Scholar 

  19. Xu Y, Sette A, Sidney J, Gendler SJ, Franco A . Tumor-associated carbohydrate antigens: a possible avenue for cancer prevention. Immunol Cell Biol 2005; 83: 440–448.

    Article  CAS  Google Scholar 

  20. Mukherjee P, Tinder TL, Basu GD, Pathangey LB, Chen L, Gendler SJ . Therapeutic efficacy of MUC1-specific cytotoxic T lymphocytes and CD137 co-stimulation in a spontaneous breast cancer model. Breast Dis 2004; 20: 53–63.

    Article  CAS  Google Scholar 

  21. Yoshida N, Abe H, Ohkuri T, Wakita D, Sato M, Noguchi D et al. Expression of the MAGE-A4 and NY-ESO-1 cancer-testis antigens and T cell infiltration in non-small cell lung carcinoma and their prognostic significance. Int J Oncol 2006; 28: 1089–1098.

    CAS  PubMed  Google Scholar 

  22. Figueiredo DL, Mamede RC, Proto-Siqueira R, Neder L, Silva Jr WA, Zago MA . Expression of cancer testis antigens in head and neck squamous cell carcinomas. Head Neck 2006; 28: 614–619.

    Article  Google Scholar 

  23. Kikuchi M, Nakao M, Inoue Y, Matsunaga K, Shichijo S, Yamana H et al. Identification of a SART-1-derived peptide capable of inducing HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes. Int J Cancer 1999; 81: 459–466.

    Article  CAS  Google Scholar 

  24. Badoual C, Hans S, Rodriguez J et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 2006; 12: 465–472.

    Article  CAS  Google Scholar 

  25. Shin KH, Kang MK, Kim RH, Kameta A, Baluda MA, Park NH . Abnormal DNA end-joining activity in human head and neck cancer. Int J Mol Med 2006; 17: 917–924.

    CAS  PubMed  Google Scholar 

  26. Pecina-Slaus N, Kljaic M, Nikuseva-Martic T . Loss of heterozygosity of APC and CDH1 genes in laryngeal squamous cell carcinoma. Pathol Res Pract 2005; 201: 557–563.

    Article  CAS  Google Scholar 

  27. Wang X, Fan M, Chen X, Wang S, Alsharif MJ, Wang L et al. Intratumor genomic heterogeneity correlates with histological grade of advanced oral squamous cell carcinoma. Oral Oncol 2006; 42: 740–744.

    Article  CAS  Google Scholar 

  28. Bavoux C, Leopoldino AM, Bergoglio V, O-Wang J, Ogi T, Bieth A et al. Up-regulation of the error-prone DNA polymerase {kappa} promotes pleiotropic genetic alterations and tumorigenesis. Cancer Res 2005; 65: 325–330.

    CAS  PubMed  Google Scholar 

  29. Chopra A, Kim TS, O-Sullivan I, Martinez D, Cohen EP . Treatment of squamous carcinoma in mice with a vaccine enriched for cells that induce immunity to squamous carcinoma-A new vaccination strategy. Int J Cancer 2006; 119: 339–348.

    Article  CAS  Google Scholar 

  30. Kim TS, Cohen EP . Immunity to breast cancer in mice immunized with fibroblasts transfected with a cDNA expression library derived from small numbers of breast cancer cells. Cancer Gene Ther 2005; 12: 890–899.

    Article  CAS  Google Scholar 

  31. Kaneko T, LePage GA, Shnitka TK . KLN205-a murine lung carcinoma cell line. In vitro 1980; 16: 884–892.

    Article  CAS  Google Scholar 

  32. de Zoeten BF, Carr-Brendel V, Cohen EP . Resistance to melanoma in mice immunized with semi-allogeneic fibroblasts transfected with genomic DNA from melanoma cells. J Immunol 1998; 160: 2915–2922.

    CAS  PubMed  Google Scholar 

  33. de Zoeten B, Carr-Brendel V, Markovic D, Taylor-Papadimitriou J, Cohen EP . Immunity to breast cancer in mice immunized with semi-allogeneic fibroblasts transfected with DNA from breast cancer cells. J Immunol 1999; 162: 6934–6941.

    CAS  PubMed  Google Scholar 

  34. Wigler M, Pellicer A, Silverstein S, Axel R, Urlaub G, Chasin L . DNA-mediated transfer of the adenine phosphoribosyl transferase locus into mammalian cells. Proc Natl Acad Sci USA 1979; 76: 1373–1376.

    Article  CAS  Google Scholar 

  35. Gilboa E . The makings of a tumor rejection antigen. Immunity 1999; 11: 263–270.

    Article  CAS  Google Scholar 

  36. Kuss I, Schaefer C, Godfrey TE, Ferris RL, Harris JM, Gooding W et al. Recent thymic emigrants and subsets of naive and memory T cells in the circulation of patients with head and neck cancer. Clin Immunol 2005; 16: 27–36.

    Article  Google Scholar 

  37. Meissner M, Reichert TE, Kunkel M, Gooding W, Whiteside TL, Ferrone S et al. Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res 2005; 11: 2552–2560.

    Article  CAS  Google Scholar 

  38. Whiteside TL . Immunobiology of head and neck cancer. Cancer Metastasis Rev 2005; 24: 95–105.

    Article  CAS  Google Scholar 

  39. Whiteside TL . Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. Semin Cancer Biol 2006; 16: 3–15.

    Article  CAS  Google Scholar 

  40. Barraclough R, Chen HJ, Davies BR, Davies MP, Ke Y, Lloyd BH et al. Use of DNA transfer in the induction of metastasis in experimental mammary systems. Biochem Soc Symp 1998; 63: 273–294.

    CAS  PubMed  Google Scholar 

  41. Kavathas P, Herzenberg LA . Stable transformation of mouse LM cells (a transformed fibroblast cell line) for human membrane T-cell differentiation antigens, HLA and B2 microglobulin: selection by fluorescence-activated cell sorting. Proc Natl Acad Sci USA 1983; 80: 524–528.

    Article  CAS  Google Scholar 

  42. Shih C, Shilo B-Z, Goldfarb MP, Dannenberg A, Weinberg RA . Passage of phenotypes of chemically transformed cells via transfection of DNA and chromatin. Proc Natl Acad Sci USA 1979; 76: 5714–5718.

    Article  CAS  Google Scholar 

  43. Shih C, Weinberg RA . Isolation of a transforming sequence from a human bladder carcinoma cell line. Cell 1982; 29: 161–169.

    Article  CAS  Google Scholar 

  44. Fanceschi S, Talamini R, Barra S, Baron AE, Negri E, Bidoli E . Smoking and drinking in relation to cancer of the oral cavity, pharynx, larynx and esophagus in northern Italy. Cancer Res 1990; 50: 6502–6507.

    Google Scholar 

  45. Yamazaki H, Inui Y, Yun CH, Guengerich FP, Shimada T . Cytochrome P450 2E1 and 2A6 enzymes as major catalysts for metabolic activation of N-nitrosodialkylamines and tobacco-related nitrosamines in human liver microsomes. Carcinogenesis 1992; 13: 1789–1794.

    Article  CAS  Google Scholar 

  46. Maecker B, von Bergwelt-Baildon MS, Anderson KS, onderheide RH, Anderson KC, Nadler LM et al. Rare naturally occurring immune responses to three epitopes from the widely expressed tumour antigens hTERT and CYP1B1 in multiple myeloma patients. Clin Exp Immunol 2005; 141: 558–562.

    Article  CAS  Google Scholar 

  47. Gribben JG, Ryan DP, Boyajian R, Urban RG, Hedley ML, Beach K et al. Unexpected association between induction of immunity to the universal tumor antigen CYP1B1 and response to next therapy. Clin Cancer Res 2005; 11: 4430–4436.

    Article  CAS  Google Scholar 

  48. Maecker B, von Bergwelt-Baildon MS, Sherr DH, Nadler LM, Schultze JL . Identification of a new HLA-A*0201-restricted cryptic epitope from CYP1B1. Int J Cancer 2005; 115: 333–336.

    Article  CAS  Google Scholar 

  49. Kan T, Yamasaki S, Kondo K, Teratani N, Kawabe A, Kaganoi J et al. A new specific gene expression in squamous cell carcinoma of the esophagus detected using representational difference analysis and cDNA microarray. Oncology 2006; 70: 25–33.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIDCR Grant number 1 RO1 DEO13970-O1A2 awarded to Dr Cohen. The use of animals in these studies was reviewed and approved by the Animal Care Committee of the University of Illinois (Approval number 04-067, expires 7/07).

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL, USA

    I O-Sullivan, A Chopra, J Huang & E P Cohen

  2. School of Life Sciences and Biotechnology, Korea University, Seoul, Korea

    T S Kim

  3. GenUs BioSystems Inc., Northbrook, IL, USA

    S Magnuson & M T Falduto

Authors
  1. I O-Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Chopra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T S Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Magnuson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M T Falduto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E P Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E P Cohen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

O-Sullivan, I., Chopra, A., Kim, T. et al. New strategy for the identification of squamous carcinoma antigens that induce therapeutic immune responses in tumor-bearing mice. Cancer Gene Ther 14, 389–398 (2007). https://doi.org/10.1038/sj.cgt.7701023

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7701023

Keywords

Search

Advanced search

Quick links