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Induction of an effective anti-tumor immune response and tumor regression by combined administration of IL-18 and Apoptin

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Abstract

Immunization strategies using plasmid DNA can potentially improve humoral and cellular immune responses that protect against cancer and infectious diseases. The chicken anemia virus-derived Apoptin protein exhibits remarkable specificity in its ability to induce apoptosis in tumor cells, but not in normal diploid cells. Interleukin-18 (IL-18) is a Th1-type cytokine that has demonstrated potential as a biological adjuvant in murine tumor models. In this study, we analyzed the anti-tumor potential and mechanism of action of simultaneous Apoptin and IL-18 gene transfer in C57BL/6 mice bearing Lewis lung carcinoma (LLC). Here we report that the growth of established tumors in mice immunized with pAPOPTIN in conjunction with pIL-18 was significantly inhibited compared with the growth of tumors in mice immunized with the empty vector (EV) or pAPOPTIN alone. Furthermore, the immunization of mice with pAPOPTIN in conjunction with pIL-18 elicited strong natural killer activity and LLC tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro. In addition, T cells from lymph nodes of mice vaccinated with pIL-18 or pAPOPTIN + pIL-18 secreted high levels of the Th1 cytokine IL-2 and IFN-γ, indicating that the regression of tumor cells is related to a Th1-type dominant immune response. These results demonstrate that vaccination with Apoptin together with IL-18 may be a novel and powerful strategy for cancer immunotherapy.

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References

  1. (2002) Chemotherapy and non-small-cell lung cancer. Drug Ther Bull 40:9–11

  2. Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky E, Jiroutek M, Johnson D (2000) Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 18:623–631

    PubMed  CAS  Google Scholar 

  3. Rana SN, Li X, Chaudry IH, Bland KI, Choudhry MA (2005) Inhibition of IL-18 reduces myeloperoxidase activity and prevents edema in intestine following alcohol and burn injury. J Leukoc Biol 77:719–728

    Article  PubMed  CAS  Google Scholar 

  4. Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, Mattson K, Manegold C, Palmer MC, Gregor A, Nguyen B, Niyikiza C, Einhorn LH (2000) Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 18:122–130

    PubMed  CAS  Google Scholar 

  5. ten Bokkel Huinink WW, Bergman B, Chemaissani A, Dornoff W, Drings P, Kellokumpu-Lehtinen PL, Liippo K, Mattson K, von Pawel J, Ricci S, Sederholm C, Stahel RA, Wagenius G, Walree NV, Manegold C (1999) Single-agent gemcitabine: an active and better tolerated alternative to standard cisplatin-based chemotherapy in locally advanced or metastatic non-small cell lung cancer. Lung Cancer 26:85–94

    Article  PubMed  CAS  Google Scholar 

  6. Hu W, Kavanagh JJ (2003) Anticancer therapy targeting the apoptotic pathway. Lancet Oncol 4:721–729

    Article  PubMed  CAS  Google Scholar 

  7. Danen-Van Oorschot AA, Zhang YH, Leliveld SR, Rohn JL, Seelen MC, Bolk MW, Van Zon A, Erkeland SJ, Abrahams JP, Mumberg D, Noteborn MH (2003) Importance of nuclear localization of apoptin for tumor-specific induction of apoptosis. J Biol Chem 278:27729–27736

    Article  PubMed  CAS  Google Scholar 

  8. Oro C, Jans DA (2004) The tumour specific pro-apoptotic factor apoptin (Vp3) from chicken anaemia virus. Curr Drug Targets 5:179–190

    Article  PubMed  CAS  Google Scholar 

  9. Poon IK, Oro C, Dias MM, Zhang J, Jans DA (2005) Apoptin nuclear accumulation is modulated by a CRM1-recognized nuclear export signal that is active in normal but not in tumor cells. Cancer Res 65:7059–7064

    Article  PubMed  CAS  Google Scholar 

  10. Maddika S, Booy EP, Johar D, Gibson SB, Ghavami S, Los M (2005) Cancer-specific toxicity of apoptin is independent of death receptors but involves the loss of mitochondrial membrane potential and the release of mitochondrial cell-death mediators by a Nur77-dependent pathway. J Cell Sci 118:4485–4493

    Article  PubMed  CAS  Google Scholar 

  11. Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4:11–22

    Article  PubMed  CAS  Google Scholar 

  12. Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K et al (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378:88–91

    Article  PubMed  CAS  Google Scholar 

  13. Micallef MJ, Yoshida K, Kawai S, Hanaya T, Kohno K, Arai S, Tanimoto T, Torigoe K, Fujii M, Ikeda M, Kurimoto M (1997) In vivo antitumor effects of murine interferon-gamma-inducing factor/interleukin-18 in mice bearing syngeneic Meth A sarcoma malignant ascites. Cancer Immunol Immunother 43:361–367

    Article  PubMed  CAS  Google Scholar 

  14. Osaki T, Peron JM, Cai Q, Okamura H, Robbins PD, Kurimoto M, Lotze MT, Tahara H (1998) IFN-gamma-inducing factor/IL-18 administration mediates IFN-gamma- and IL-12-independent antitumor effects. J Immunol 160:1742–1749

    PubMed  CAS  Google Scholar 

  15. Marshall DJ, Rudnick KA, McCarthy SG, Mateo LR, Harris MC, McCauley C, Snyder LA (2006) Interleukin-18 enhances Th1 immunity and tumor protection of a DNA vaccine. Vaccine 24:244–253

    Article  PubMed  CAS  Google Scholar 

  16. Nakamura S, Otani T, Ijiri Y, Motoda R, Kurimoto M, Orita K (2000) IFN-gamma-dependent and -independent mechanisms in adverse effects caused by concomitant administration of IL-18 and IL-12. J Immunol 164:3330–3336

    PubMed  CAS  Google Scholar 

  17. Tan F, Zhang Y, Xu Y, Liu W, Zhang Y, Ouyang H (1998) Amplification and cloning of genomic DNA of apoptin. Chin J Vet Sci 18:421–423

    CAS  Google Scholar 

  18. Mi Z, Jin N, Gong W, Xue L, Lian H, Xie L, Li P (2003) Construction and expression of the nucleic acid vaccine pVVP3 and pVHN and its effect on tumor cell. Chin J Biochem Mol Biol 19:704–708

    CAS  Google Scholar 

  19. Wu J, Wu Y, Yang BB (2002) Anticancer activity of Hemsleya amabilis extract. Life Sci 71:2161–2170

    Article  PubMed  CAS  Google Scholar 

  20. Kiechle FL, Malinski T (1993) Nitric oxide: biochemistry, pathophysiology, and detection. Am J Clin Pathol 100:567–575

    PubMed  CAS  Google Scholar 

  21. Dasgupta S, Tripathi PK, Bhattacharya-Chatterjee M, O’Malley BW Jr, Chatterjee SK (2003) Recombinant vaccinia virus expressing IL-2 generates effective anti-tumor responses in an orthotopic murine model of head and neck carcinoma. Mol Ther 8:238–248

    Article  PubMed  CAS  Google Scholar 

  22. Fischer U, Schulze-Osthoff K (2005) New approaches and therapeutics targeting apoptosis in disease. Pharmacol Rev 57:187–215

    Article  PubMed  CAS  Google Scholar 

  23. van der Eb MM, Pietersen AM, Speetjens FM, Kuppen PJ, van de Velde CJ, Noteborn MH, Hoeben RC (2002) Gene therapy with apoptin induces regression of xenografted human hepatomas. Cancer Gene Ther 9:53–61

    Article  PubMed  Google Scholar 

  24. Guelen L, Paterson H, Gaken J, Meyers M, Farzaneh F, Tavassoli M (2004) TAT-apoptin is efficiently delivered and induces apoptosis in cancer cells. Oncogene 23:1153–1165

    Article  PubMed  CAS  Google Scholar 

  25. Pietersen AM, van der Eb MM, Rademaker HJ, van den Wollenberg DJ, Rabelink MJ, Kuppen PJ, van Dierendonck JH, van Ormondt H, Masman D, van de Velde CJ, van der Eb AJ, Hoeben RC, Noteborn MH (1999) Specific tumor-cell killing with adenovirus vectors containing the apoptin gene. Gene Ther 6:882–892

    Article  PubMed  CAS  Google Scholar 

  26. Wallace-Brodeur RR, Lowe SW (1999) Clinical implications of p53 mutations. Cell Mol Life Sci 55:64–75

    Article  PubMed  CAS  Google Scholar 

  27. Reed JC (1995) Bcl-2: prevention of apoptosis as a mechanism of drug resistance. Hematol Oncol Clin North Am 9:451–473

    PubMed  CAS  Google Scholar 

  28. Hickman JA, Potten CS, Merritt AJ, Fisher TC (1994) Apoptosis and cancer chemotherapy. Philos Trans R Soc Lond B Biol Sci 345:319–325

    PubMed  CAS  Google Scholar 

  29. Nakamura K, Okamura H, Wada M, Nagata K, Tamura T (1989) Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun 57:590–595

    PubMed  CAS  Google Scholar 

  30. Fukumoto H, Nishio M, Nishio K, Heike Y, Arioka H, Kurokawa H, Ishida T, Fukuoka K, Nomoto T, Ohe Y, Saijo N (1997) Interferon-gamma-inducing factor gene transfection into Lewis lung carcinoma cells reduces tumorigenicity in vivo. Jpn J Cancer Res 88:501–505

    PubMed  CAS  Google Scholar 

  31. Hashimoto W, Osaki T, Okamura H, Robbins PD, Kurimoto M, Nagata S, Lotze MT, Tahara H (1999) Differential antitumor effects of administration of recombinant IL-18 or recombinant IL-12 are mediated primarily by Fas–Fas ligand- and perforin-induced tumor apoptosis, respectively. J Immunol 163:583–589

    PubMed  CAS  Google Scholar 

  32. Colombo MP, Trinchieri G (2002) Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev 13:155–168

    Article  PubMed  CAS  Google Scholar 

  33. Smyth MJ, Taniguchi M, Street SE (2000) The anti-tumor activity of IL-12: mechanisms of innate immunity that are model and dose dependent. J Immunol 165:2665–2670

    PubMed  CAS  Google Scholar 

  34. Dasgupta S, Bhattacharya-Chatterjee M, O’Malley BW Jr, Chatterjee SK (2006) Recombinant vaccinia virus expressing interleukin-2 invokes anti-tumor cellular immunity in an orthotopic murine model of head and neck squamous cell carcinoma. Mol Ther 13:183–193

    Article  PubMed  CAS  Google Scholar 

  35. Russo V, Tanzarella S, Dalerba P, Rigatti D, Rovere P, Villa A, Bordignon C, Traversari C (2000) Dendritic cells acquire the MAGE-3 human tumor antigen from apoptotic cells and induce a class I-restricted T cell response. Proc Natl Acad Sci USA 97:2185–2190

    Article  PubMed  CAS  Google Scholar 

  36. Sin JI, Kim JJ, Boyer JD, Ciccarelli RB, Higgins TJ, Weiner DB (1999) In vivo modulation of vaccine-induced immune responses toward a Th1 phenotype increases potency and vaccine effectiveness in a herpes simplex virus type 2 mouse model. J Virol 73:501–509

    PubMed  CAS  Google Scholar 

  37. Woldbaek PR, Tonnessen T, Henriksen UL, Florholmen G, Lunde PK, Lyberg T, Christensen G (2003) Increased cardiac IL-18 mRNA, pro-IL-18 and plasma IL-18 after myocardial infarction in the mouse: a potential role in cardiac dysfunction. Cardiovasc Res 59:122–131

    Article  PubMed  CAS  Google Scholar 

  38. Triccas JA, Sun L, Palendira U, Britton WJ (2002) Comparative effects of plasmid-encoded interleukin 12 and interleukin 18 on the protective efficacy of DNA vaccination against Mycobacterium tuberculosis. Immunol Cell Biol 80:346–350

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Dr. Ying Li, University of Virginia, for her valuable assistance and suggestions. We also thank ELIXIGEN Co. for excellent technical assistance. This work was supported by a grant (No. G1999011902) from National Key Foundation Project, The Ministry of Science and Technology, the People’s Republic of China.

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Correspondence to Ningyi Jin.

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Lian, H., Jin, N., Li, X. et al. Induction of an effective anti-tumor immune response and tumor regression by combined administration of IL-18 and Apoptin. Cancer Immunol Immunother 56, 181–192 (2007). https://doi.org/10.1007/s00262-006-0178-y

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  • DOI: https://doi.org/10.1007/s00262-006-0178-y

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