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  • Original Article
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Gene therapy by membrane-expressed superantigen for α-fetoprotein-producing hepatocellular carcinoma

Abstract

Staphylococcus enterotoxin A (SEA) is a powerful immunostimulant, which can stimulate T cells bearing certain T-cell receptor β-chain variable regions, when bound to major histocompatibility complex II molecules. In vivo administration of intact superantigen in sufficient therapeutic amounts risks unwanted cytotoxicity against normal cells. In this study, we used SEA fused with CD80 transmembrane region (named as SEAtm) driven by α-fetoprotein (AFP) enhancer/promoter to reduce toxicity and to improve safety and efficiency in the application of SEA. We demonstrated that SEAtm by adenovirus from the AFP enhancer/promoter (AdAFPSEA) could be expressed on the surface of AFP-producing cell line Hepa1-6 instead of non-AFP-producing cell lines. Hepa1-6 infected by recombinant adenovirus stimulated proliferation of splenocytes and activated CD4+ and CD8+ T cells in vitro. After AdAFPSEA was injected into the subcutaneously established hepatoma in vivo, the expression of SEA was detected in tumor tissues, which subsequently induced tumor-specific cytotoxic T cells in spleen. Moreover, hepatocellular carcinoma (HCC) xenografts were suppressed by treatment with AdAFPSEA and the survival time of treated mice was prolonged. These findings suggest that membrane-expressed SEA by adenovirus from AdAFPSEA can generate stronger local and systemic antitumor responses against HCC.

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References

  1. Melief CJ . Tumor eradication by adoptive transfer of cytotoxic T lymphocytes. Adv Cancer Res 1992; 58: 143–175.

    Article  CAS  Google Scholar 

  2. Baskar S . Gene-modified tumor cells as cellular vaccine. Cancer Immunol Immunother 1996; 43: 165–173.

    Article  CAS  Google Scholar 

  3. Putzer BM, Stiewe T, Rodicker F, Schildgen O, Ruhm S, Dirsch O et al. Large nontransplanted hepatocellular carcinoma in woodchucks: treatment with adenovirus-mediated delivery of interleukin 12/B7.1 genes. J Natl Cancer Inst 2001; 93: 472–479.

    Article  CAS  Google Scholar 

  4. Kotb M . Bacterial pyrogenic exotoxins as superantigens. Clin Microbiol Rev 1995; 8: 411–426.

    Article  CAS  Google Scholar 

  5. Dohlsten M, Lando PA, Hedlund G, Trowsdale J, Kalland T . Targeting of human cytotoxic T lymphocytes to MHC class II-expressing cells by staphylococcal enterotoxins. Immunology 1990; 71: 96–100.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Dohlsten M, Sundstedt A, Bjorklund M, Hedlund G, Kalland T . Superantigen-induced cytokines suppress growth of human colon-carcinoma cells. Int J Cancer 1993; 54: 482–488.

    Article  CAS  Google Scholar 

  7. Li ZS, Yang XW, Chen Z, Dong HL, Ye J, Qu P et al. In vivo tumor co-transfection with superantigen and CD80 induces systemic immunity without tolerance and prolongs survival in mice with hepatocellular carcinoma. Cancer Biol Ther 2004; 9: 660–666.

    Article  Google Scholar 

  8. Nielsen SE, Zeuthen J, Lund B, Persson B, Alenfall J, Hansen HH . Phase I study of single, escalating doses of a superantigen-antibody fusion protein (PNU-214565) in patients with advanced colorectal or pancreatic carcinoma. J Immunother 2000; 23: 146–153.

    Article  CAS  Google Scholar 

  9. Cheng JD, Babb JS, Langer C, Aamdal S, Robert F, Engelhardt LR et al. Individualized patient dosing in phase I clinical trials: the role of escalation with overdose control in PNU-214936. J Clin Oncol 2004; 22: 602–609.

    Article  CAS  Google Scholar 

  10. Wahlsten JL, Mills CD, Ramakrishnan S . Antitumor response elicited by a superantigen-transmembrane sequence fusion protein anchored onto tumor cells. J Immunol 1998; 161: 6761–6767.

    CAS  PubMed  Google Scholar 

  11. Litton MJ, Dohlsten M, Hansson J, Rosendahl A, Ohlsson L, Kalland T et al. Tumor therapy with an antibody-targeted superantigen generation a dichotomy between local and systemic immune responses. Am J Pathol 1997; 150: 1607–1618.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Lu SY, Sui YF, Li ZS, Pan CE, Ye J, Wang WY . Construction of a regulable gene therapy vector targeting for hepatocellular carcinoma. World J Gastroenterol 2003; 9: 688–691.

    Article  CAS  Google Scholar 

  13. Nakaya H, Ishizu A, Ikeda H, Tahara M, Shindo J, Itoh R et al. In vitro model of suicide gene therapy for alpha-fetoprotein-producing gastric cancer. Anticancer Res 2003; 23: 3795–3800.

    CAS  PubMed  Google Scholar 

  14. Song JS . Adenovirus-mediated suicide SCLC gene therapy using the increased activity of the hTERT promoter by the MMRE and SV40 enhancer. Biosci Biotechnol Biochem 2005; 69: 56–62.

    Article  CAS  Google Scholar 

  15. Spear BT . Alpha-fetoprotein gene regulation: lessons from transgenic mice. Semin Cancer Bio 1999; 19: 109–116.

    Article  Google Scholar 

  16. Kawabata K, Sakurai F, Yamaguchi T, Hayakawa T, Mizuguchi H . Efficient gene transfer into mouse embryonic stem cells with adenovirus vectors. Mol Ther 2005; 12: 547–554.

    Article  CAS  Google Scholar 

  17. Miller WH, Brosnan MJ, Graham D, Nicol CG, Morecroft I, Channon KM et al. Targeting endothelial cells with adenovirus expressing nitric oxide synthase prevents elevation of blood pressure in stroke-prone spontaneously hypertensive rats. Mol Ther 2005; 12: 321–327.

    Article  CAS  Google Scholar 

  18. Green JM, Turka LA, June CH, Thompson CB . CD28 and staphylococcal enterotoxins synergize to induce MHC-independent T-cell proliferation. Cell Immunol 1992; 145: 11–20.

    Article  CAS  Google Scholar 

  19. Taub D, Rogers TJ . Direct activation of murine T cells by staphylococcal enterotoxins. Cell Immunol 1992; 140: 267–281.

    Article  CAS  Google Scholar 

  20. Ihle J, Holzer U, Krull F, Dohlsten M, Kalland T, Niethammer D et al. Antibody-targeted superantigens induce lysis of major histocompatibility complex class II-negative T-cell lines. Cancer Res 1995; 55: 623–628.

    CAS  PubMed  Google Scholar 

  21. Holzer U, Bethge W, Krull F, Ihle J, Handgretinger R, Reisfeld RA et al. Superantigen-staphylococcal-enterotoxin-A-dependent and antibody-targeted lysis of GD2-positive neuroblastoma cells. Cancer Immunol Immunother 1995; 41: 129–136.

    CAS  PubMed  Google Scholar 

  22. Dighe AS, Richards E, Old LJ, Schreiber RD . Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN-γreceptors. Immunity 1994; 1: 447.

    Article  CAS  Google Scholar 

  23. Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ et al. Demonstration of an interferon-γ-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 1998; 95: 7556.

    Article  CAS  Google Scholar 

  24. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old J et al. IFN-γand lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410: 1107.

    Article  CAS  Google Scholar 

  25. Street SE, Cretney E, Smyth MJ . Perforin and interferon-γactivities independently control tumor initiation, growth, and metastasis. Blood 2001; 97: 192.

    Article  CAS  Google Scholar 

  26. Street SE, Trapani JA, MacGregor D, Smyth MJ . Suppression of lymphoma and epithelial malignancies effected by interferon-γ. J Exp Med 2002; 196: 129.

    Article  CAS  Google Scholar 

  27. Nishimura T, Nakui M, Sato M, Iwakabe K, Kitamura H, Sekimoto M et al. The critical role of Th1-dominant immunity in tumorimmunology. Cancer Chemother Pharmacol 2000; 46: S52.

    Article  CAS  Google Scholar 

  28. Rosendahl A, Kristensson K, Hansson J, Riesbeck K, Kalland T, Dohlsten M . Perforin and IFN-γ are involved in the antitumor effects of antibody-targeted superantigens. J Immunol 1998; 160: 5309.

    CAS  PubMed  Google Scholar 

  29. Melief CJ, Kast WM . T-cell immunotherapy of tumors by adoptive transfer of cytotoxic T lymphocytes and by vaccination with minimal essential epitopes. Immunol Rev 1995; 45: 167.

    Article  Google Scholar 

  30. Sogaard M, Hansson J, Litton MJ, Ohlsson L, Rosendahl A, Lando PA et al. Antibody-targeted superantigens in cancer immunotherapy. Immunotechnology 1996; 2: 151–162.

    Article  CAS  Google Scholar 

  31. Dohlsten M, Sundstedt A, Björklund M, Hedlund G, Kalland T . Superantigen-induced cytokines suppress growth of human colon-carcinoma cells. Int J Cancer 1993; 54: 482–488.

    Article  CAS  Google Scholar 

  32. Dohlsten M, Hedlund G, Akerblom E, Lando PA, Kalland T . Monoclonal antibody-targeted superantigens: a different class of anti-tumor agents. Proc Natl Acad Sci USA 1991; 88: 9287–9291.

    Article  CAS  Google Scholar 

  33. Lando PA, Dohlsten M, Hedlund G, Akerblom E, Kalland T . T cell killing of human colon carcinomas by monoclonal-antibody targeted superantigens. Cancer Immunol Immunother 1993; 36: 223–228.

    Article  CAS  Google Scholar 

  34. Lando PA, Hedlund G, Dohlsten M, Kalland T . Bacterial superantigens as anti-tumor agents: induction of tumor cytotoxicity in human lymphocytes by staphylococcal enterotoxin A. Cancer Immunol Immunother 1991; 3: 231–237.

    Article  Google Scholar 

  35. Dohlsten M, Lando PA, Bjork P, Abrahmsen L, Ohlsson L, Lind P et al. Immunotherapy of human colon cancer by antibody-targeted superantigens. Cancer Immunol Immunother 1995; 41: 162–168.

    Article  CAS  Google Scholar 

  36. Nakabeppu Y, Oda S, Sekiguchi M . Proliferative activation of quiescent Rat-1 A cells by delta FosB. Mol Cell Biol 1993; 13: 4157–4166.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the China National Natural Science Foundation (no. 39770827 and 30271474).

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Correspondence to Y Sui.

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Si, S., Sun, Y., Li, Z. et al. Gene therapy by membrane-expressed superantigen for α-fetoprotein-producing hepatocellular carcinoma. Gene Ther 13, 1603–1610 (2006). https://doi.org/10.1038/sj.gt.3302823

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