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:

Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma

Cancer Gene Therapy volume 10, pages 481–490 (2003)Cite this article

Abstract

Malignant mesothelioma (MM) is a lethal tumor linked with a prior exposure to asbestos in which limited progress has been made so far using conventional therapies. MM is an example of a “nonimmunogenic” tumor characterized by a fibrous stroma and an absence of infiltrating T lymphocytes. High levels of transforming growth factor-beta (TGF-β) produced by mesothelioma cells have been related to the immune tolerance towards the tumor. In order to evaluate the effect of local delivery of cytokines such as interferon gamma (IFN-γ) by gene transfer, we characterized and used a murine model, AK7, which appeared very similar to human mesothelioma. AK7 cells expressed low levels of major histocompatibility class I and class II antigens and secreted high levels of latent TGF-β. The TGF-β pathway in AK7 cells is operative but inefficient because endogenous TGF-β is predominantly inactive. Treatment of pre-established AK7 tumors by direct intratumoral injection of an adenovirus vector expressing murine IFN-γ, Ad.mIFN-γ, led to significant tumor regression. Peripheral tumor infiltration by CD4+ and CD8+ T lymphocytes in the treated tumors appeared to be because of the induction of an immune response. Tumor relapse was observed, which could be due to local TGF-β secretion by remaining tumor cells.

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
Figure 7

Similar content being viewed by others

References

  1. Wagner JC, Sleggs CA, Marchand P . Diffuse pleural mesothelioma and asbestos exposure in North Western Cape Province. Br J Ind Med. 1960;17:260–271.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Craighead JE, Mossman BT . The pathogenesis of asbestos-associated diseases. N Eng J Med. 1982;306:1446–1455.

    Article  CAS  Google Scholar 

  3. Sterman DH, Kaiser LR, Albeida SM . Gene therapy for malignant pleural mesothelioma. Hematol Oncol Clin North Am. 1998;12:553–568.

    Article  CAS  Google Scholar 

  4. Ramael M, Van Meerbeeck JV, Van Marck EV . Mesothelioma, currents insights. Cancer J. 1994;7:174–180.

    Google Scholar 

  5. Kumar-Singh S, Weyler J, Martin MJH, et al. Angiogenic cytokines in mesothelioma: a study of VEGF, FGF-1 and -2, and TGFβ expression. J Pathol. 1999;189:72–78.

    Article  CAS  Google Scholar 

  6. Ruffie PA . Pleural mesothelioma. Curr Opin Onc. 1991;3:328–334.

    Article  CAS  Google Scholar 

  7. Peto J, Hodgson JT, Matthews FE, Jones JR . Continuing increase in mesothelioma mortality in britain. Lancet. 1995;345:535–539.

    Article  CAS  Google Scholar 

  8. Ulloa L, Doody J, Massague J . Inhibition of transforming growth factor-β/SMAD signalling by the interferon-gamma/STAT pathway. Nature. 1999;397:710–713.

    Article  CAS  Google Scholar 

  9. Caminschi I, Venetsanakos E, Leong CC, et al. Cytokine gene therapy of mesothelioma. Immune and antitumoral effects of transfected interleukin-12. Am J Respir Cell Mol Biol. 1999;21:347–356.

    Article  CAS  Google Scholar 

  10. Law MR, Hodson ME, Heard BE . Malignant mesothelioma of the pleura: relation between histological type and clinical behaviour. Thorax. 1982;37:810–815.

    Article  CAS  Google Scholar 

  11. Graham FL, Van Der Eb EJ . A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973;52:456–467.

    Article  CAS  Google Scholar 

  12. Graham FL, Smiley J, Russel WC, Nairu R . Characteristics of a human cell line transformed by the DNA from human adenovirus 5. J Gen Virol. 1977;36:59–72.

    Article  CAS  Google Scholar 

  13. Cordier L, Duffour MT, Sabourin JC, et al. Complete recovery of mice from a pre-established tumor by direct intratumoral delivery of an adenovirus vector harboring the murine IL-2 gene. Gene Ther. 1995;2:16–21.

    CAS  PubMed  Google Scholar 

  14. Josien R, Douillard P, Guillot C, et al. A critical role for transforming growth factor-β in donor transfusion-induced allograft tolerance. J Clin Invest. 1998;102:1920–1926.

    Article  CAS  Google Scholar 

  15. Monti G, Jaurand MC, Monnet I, et al. Intrapleural production of interleukin 6 during mesothelioma and its modulation by γ-interferon treatment. Cancer Res. 1994;54:4419–4423.

    CAS  PubMed  Google Scholar 

  16. Fernandez N, Levraud JP, Haddada H, et al. High frequency of specific CD8+ T cells in the tumor and blood is associated with efficient local Il-12 therapy of cancer. J Immunol. 1999;162:609–617.

    CAS  PubMed  Google Scholar 

  17. Baratin M, Ziol M, Romieu R, et al. Regression of primary hepatocarcinoma in cancer-prone transgenic mice by local interferon-gamma delivery is associated with macrophages recruitment and nitric oxide production. Cancer Gene Ther. 2001;8:193–202.

    Article  CAS  Google Scholar 

  18. Johansson L, Linden CJ . Aspects of histopathologic subtype as a prognostic factor in 785 pleural mesotheliomas. Chest. 1996;109:109–114.

    Article  CAS  Google Scholar 

  19. Barrack ER . TGF beta in prostate cancer: a growth inhibitor that can enhance tumorigenicity. Prostate. 1997;31:61–70.

    Article  CAS  Google Scholar 

  20. Addison CL, Braciak T, Raltson R, et al. Intratumoral injection of an adenovirus expressing interleukin 2 induces regression and immunity in a murine breast cancer model. Proc Natl Acad Sci USA. 1995;92:8522–8526.

    Article  CAS  Google Scholar 

  21. Wallach D, Fellous M, Revel M . Preferential effect of interferon-gamma on the synthesis of HLA antigens and their mRNAs in human cells. Nature. 1982;299:833–836.

    Article  CAS  Google Scholar 

  22. Rosa F, Hatat D, Abadie A, et al. Differential regulation of HLA-DR mRNAs and cell surface antigens by interferon. EMBO J. 1983;2:1585–1589.

    Article  CAS  Google Scholar 

  23. Collins T, Korman AJ, Wake CT, et al. Immune interferon activates multiple class II major histocompatibility complex genes and the associated invariant chain gene in human endothelial cells and dermal fibroblasts. Proc Natl Acad Sci USA. 1984;81:4917–4921.

    Article  CAS  Google Scholar 

  24. Odaka M, Sterman DH, Wiewrodt R, et al. Eradication of peritoneal and distant tumor by adenovirus-mediated interferon-β gene therapy is attributable to induction of systemic immunity. Cancer Res. 2001;61:6201–6212.

    CAS  PubMed  Google Scholar 

  25. Gerwin BI, Lechner JF, Reddel RR, et al. Comparison of production of transforming growth factor-B and platelet-derived growth factor by normal human mesothelioma cells and mesothelioma cell lines. Cancer Res. 1987;47:6180–6184.

    CAS  PubMed  Google Scholar 

  26. Fitzpatrick DR, Bielefeld-Ohmann H, Himbeck RP, et al. Transforming growth factor-beta: antisense RNA-mediated inhibition affects anchorage-independent growth, tumorigenicity and tumor-infiltrating T-cells in malignant mesothelioma. Growth Factors. 1994;11:29–44.

    Article  CAS  Google Scholar 

  27. Torre-Amione G, Beauchamp RD, Koeppen H, et al. A highly immunogenic tumor transfected with a murine transforming growth factor type β1 cDNA escapes immune surveillance. Proc Natl Acad Sci USA. 1990;87:1486–1490.

    Article  CAS  Google Scholar 

  28. Vodovotz Y, Bogdan C, Paik J, et al. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor B. J Exp Med. 1993;178:605–613.

    Article  CAS  Google Scholar 

  29. Bielefeldt-Ohmann H, Fitzpatrick DR, Marzo AL, et al. Patho- and immunobiology of malignant mesothelioma: characterisation of tumor infiltrating leucocytes and cytokine production in a murine model. Cancer Immunol Immunother. 1994;39:347–359.

    Article  CAS  Google Scholar 

  30. Serve H, Steinhauser G, Oberberg D, et al. Studies on the interaction between interleukin 6 and human malignant nonhematopoietic cell lines. Cancer Res. 1991;51:3862–3866.

    CAS  PubMed  Google Scholar 

  31. Higashihara M, Sunaga S, Tange T, et al. Increased secretion of interleukin-6 in malignant mesothelioma cells from a patient with marked thrombocytosis. Cancer. 1992;70:2105–2108.

    Article  CAS  Google Scholar 

  32. Schmitter D, Lauber B, Fagg B, et al. Hematopoietic growth factors secreted by seven human pleural mesothelioma cell lines: interleukin-6 production as a common feature. Int J Cancer. 1992;51:296–301.

    Article  CAS  Google Scholar 

  33. Bielefeldt-Ohmann H, Marzo AL, Himbeck RP, et al. Interleukin-6 involvement in mesothelioma pathobiology: inhibition by interferon γ immunotherapy. Cancer Immunol Immunother. 1995;40:241–250.

    Article  CAS  Google Scholar 

  34. Walker C, Everitt J, Ferriola PC, et al. Autocrine growth stimulation by transforming growth factor a in asbestos-transformed rat mesothelioma cells. Cancer Res. 1995;55:530–536.

    CAS  PubMed  Google Scholar 

  35. Versnel MA, Claesson-Welsh L, Hammacher A, et al. Human malignant mesothelioma cell lines express PDGF B-receptors whereas cultured normal mesothelioma cells express predominantly PDGF α-receptors. Oncogene. 1991;6:2005–2011.

    CAS  PubMed  Google Scholar 

  36. Smythe WR, Kaiser LR, Hwang HC, et al. Successful adenovirus-mediated gene transfer in an in vivo model of human malignant mesothelioma. Ann Thorac Surg. 1994;57:1395–401.

    Article  CAS  Google Scholar 

  37. Boylan AM, Sanan DA, Sheppard D, et al. Vitronectin enhances internalization of crocidolite asbestos by rabbit pleural mesothelial cells via the integrin alpha v beta 5. J Clin Invest. 1995;96:1987–2001.

    Article  CAS  Google Scholar 

  38. Smythe WR, Hwang HC, Elshami AA, et al. Treatment of experimental human mesothelioma using adenovirus transfer of the herpes simplex thymidine kinase gene. Ann Surg. 1995;222:78–86.

    Article  CAS  Google Scholar 

  39. Hwang HC, Smythe WR, Elshami AA, et al. Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer. Am J Resp Cell Mol Biol. 1995;13:7–16.

    Article  CAS  Google Scholar 

  40. Kucharczuck JC, Elshami AA, Zhang HB, et al. Pleural-based mesothelioma in immune competent rats: a model to study adenoviral gene transfer. Ann Thorac Surg. 1995;60:593–598.

    Article  Google Scholar 

  41. Elshami AA, Kucharczu JC, Zhang HB, et al. Treatment of pleural mesothelioma in an immunocompetent rat model utilizing adenoviral transfer of the herpes simplex virus thymidine kinase gene. Hum Gene Ther. 1996;7:141–148.

    Article  CAS  Google Scholar 

  42. Boulanger P . Cell receptors for human adenoviruses. J Soc Biol. 1999;193:77–84.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the CNRS, the Association pour la Recherche sur le Cancer (ARC), the Ligue Nationale Contre le Cancer, the Institut Gustave Roussy, the Assistance pubique-hopitaux de Paris (AP-HP), the Fondation pour la recherche médicale (FRM) (LV), and by a research grant (RO1 ES 03189) from the National Institute of Environmental Health Sciences (AK). MAA had a MRC fellowship. We thank Patrice Ardouin and all the staff of the laboratory of animal experimentation (IGR), Jean-Pierre Levraud for providing oligonucleotides and his help for PCR analysis and Professor CH Heldin for providing the antibodies specific to Smad7 and phosphorylated Smad2. We also thank Dr J Dando and Professor Zaghouani for corrections of the manuscript. We are grateful to the Vector Core of the University Hospital of Nantes supported by the Association Française contre les Myopathies (AFM) for providing the Ad.TGFβ vector.

LCK present address: cell genesys, Inc, South San Francisco, CA 94080, USA

Author information

Authors and Affiliations

  1. Institut Gustave Roussy, Villejuif, 94805, Cedex, France

    Laurence Cordier Kellerman, Laurence Valeyrie, Nadine Fernandez, Paule Opolon, Jean-Christophe Sabourin, Eve Maubec, Mohamed Amine Abina, Vincent Descamps & Hédi Haddada

  2. Transgene, Strasbourg, France

    Pierre Le Roy

  3. Department of Pathology and Laboratory Medicine, Brown University, Providence, 02912, Rhode Island, USA

    Agnes Kane

  4. Departement de microbiologie et d'immunologie, Université de Montreal, Ont., Canada

    Mohamed Amine Abina

  5. Hopital Bichat, Paris, France

    Agnes Legrand & Vincent Descamps

Authors
  1. Laurence Cordier Kellerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laurence Valeyrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nadine Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paule Opolon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-Christophe Sabourin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eve Maubec
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pierre Le Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Agnes Kane
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Agnes Legrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mohamed Amine Abina
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Vincent Descamps
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hédi Haddada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hédi Haddada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cordier Kellerman, L., Valeyrie, L., Fernandez, N. et al. Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma. Cancer Gene Ther 10, 481–490 (2003). https://doi.org/10.1038/sj.cgt.7700594

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700594

Keywords

This article is cited by

Search

Advanced search

Quick links