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.

  • Research Article
  • Published:

Therapeutic and specific antitumor immunity induced by co-administration of immature dendritic cells and adenoviral vector expressing biologically active IL-18

Gene Therapy volume 9, pages 1480–1486 (2002)Cite this article

Abstract

Interleukin-18 is a potent cytokine expressed early in the immune response following cleavage in activated composes. We have investigated the in vivo antitumor effects of intratumoral (i.t.) administration of an adenoviral vector expressing biologically active murine interleukin (IL)-18 (Ad.PTH.IL-18). Substantial antitumor effects were observed when established MCA205 fibrosarcoma was treated in syngeneic immunocompetent mice with intratumoral injection of Ad.PTH.IL-18 (P = 0.0025 versus control vector treatment), generating potent cytotoxic T lymphocytes (CTLs) in culture. In contrast, the antitumor effect was absent, and cytotoxic activity was significantly less (P = 0.021) in gld mice (Fas ligand deficient). To enhance the in vivo antitumor activity of the treatment using Ad.PTH.IL-18, we co-injected immature DC and Ad.PTH.IL-18 i.t. into established, day 7 MCA205 fibrosarcoma and MC38 adenocarcinoma. Co-injection of both Ad.PTH.IL-18 and DC was associated with complete abrogation of injected tumors. Furthermore, the antitumor effects were also observed on distant tumors inoculated i.d. in the contralateral flank of the animal. The induced cytolytic activity was tumor-specific and MHC class I-restricted. As we have previously demonstrated in vitro (Tanaka F et al, Cancer Res 2000; 60: 4838–4844) and consistent with these findings in vivo, NK, T and dendritic cells coactivately mediate the IL-18 enhanced antitumor effect. This study suggests that the coactivate strategy could be used in the clinical setting to treat patients with 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

References

  1. Okamura H et al. Cloning of a new cytokine that induces IFN-gamma production by T cells Nature 1995 378: 88–91

    Article  CAS  PubMed  Google Scholar 

  2. Okamura H et al. A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock Infect Immun 1995 63: 3966–3972

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Okamoto I et al. Development of CD8+ effector T cells is differentially regulated by IL-18 and IL-12 J Immunol 1999 162: 3202–3211

    CAS  PubMed  Google Scholar 

  4. Dao T, Mehal WZ, Crispe IN . IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells J Immunol 1998 161: 2217–2222

    CAS  PubMed  Google Scholar 

  5. Hashimoto W et al. 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 1999 163: 583–589

    CAS  PubMed  Google Scholar 

  6. Hoshino T, Wiltrout RH, Young HA . IL-18 is a potent coinducer of IL-13 in NK and T cells: a new potential role for IL-18 in modulating the immune response J Immunol 1999 162: 5070–5077

    CAS  PubMed  Google Scholar 

  7. Hoshino T et al. In vivo administration of IL-18 can induce IgE production through Th2 cytokine induction and up-regulation of CD40 ligand (CD154) expression on CD4+ T cells Eur J Immunol 2000 30: 1998–2006

    Article  CAS  PubMed  Google Scholar 

  8. Leite-De-Moraes MC . IL-18 enhances IL-4 production by ligand-activated NKT lymphocytes: a pro-Th2 effect of IL-18 exerted through NKT cells J Immunol 2001 166: 945–951

    Article  CAS  PubMed  Google Scholar 

  9. Osaki T et al. IFN-gamma-inducing factor/IL-18 administration mediates IFN-gamma- and IL-12-independent antitumor effects J Immunol 1998 160: 1742–1749

    CAS  PubMed  Google Scholar 

  10. Micallef MJ et al. In vivo antitumor effects of murine interferon-gamma-inducing factor/interleukin-18 in mice bearing syngeneic Meth A sarcoma malignant ascites Cancer Immunol Immunother 1997 43: 361–367

    Article  CAS  PubMed  Google Scholar 

  11. Osaki T et al. Potent antitumor effects mediated by local expression of the mature form of the interferon-gamma inducing factor, interleukin-18 (IL-18) Gene Therapy 1999 6: 808–815

    Article  CAS  PubMed  Google Scholar 

  12. Tanaka F et al. Rapid generation of potent and tumor-specific cytotoxic T lymphocytes by interleukin 18 using dendritic cells and natural killer cells Cancer Res 2000 60: 4838–4844

    CAS  PubMed  Google Scholar 

  13. Hirao M et al. CC chemokine receptor-7 on dendritic cells is induced after interaction with apoptotic tumor cells: critical role in migration from the tumor site to draining lymph nodes Cancer Res 2000 60: 2209–2217

    CAS  PubMed  Google Scholar 

  14. Steinman RM . The dendritic cell system and its role in immunogenicity Annu Rev Immunol 1991 9: 271–296

    Article  CAS  PubMed  Google Scholar 

  15. Mayordomo JI et al. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity Nat Med 1995 1: 1297–1302

    Article  CAS  PubMed  Google Scholar 

  16. Zitvogel L et al. Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation and T helper cell 1-associated cytokines J Exp Med 1996 183: 87–97

    Article  CAS  PubMed  Google Scholar 

  17. Porgador A, Snyder D, Gilboa E . Induction of antitumor immunity using bone marrow-generated dendritic cells J Immunol 1996 156: 2918–2926

    CAS  PubMed  Google Scholar 

  18. Zhang T et al. Interleukin-12 (IL-12) and IL-18 synergistically induce the fungicidal activity of murine peritoneal exudate cells against Cryptococcus neoformans through production of gamma interferon by natural killer cells Infect Immun 1997 65: 3594–3599

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cai G, Kastelein R, Hunter CA . Interleukin-18 (IL-18) enhances innate IL-12-mediated resistance to Toxoplasma gondii Infect Immun 2000 68: 6932–6938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Coughlin CM et al. Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis J Clin Invest 1998 101: 1441–1452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Carbone E et al. Recognition of autologous dendritic cells by human NK cells Eur J Immunol 1999 29: 4022–4029

    Article  CAS  PubMed  Google Scholar 

  22. Wilson LJ et al. Targetting of human dendritic cells by autologous NK cells J Immunol 1999 163: 6365–6370

    CAS  PubMed  Google Scholar 

  23. Gerosa F et al. Reciprocal activating interaction between natural killer cells and dendritic cells J Exp Med 2002 195: 327–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Piccioli D, Sbrana S, Melandri E, Valiante ND . Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells J Exp Med 2002 195: 335–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ferlazzo G et al. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells J Exp Med 2002 195: 343–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang Q et al. Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma Gene Therapy 2001 8: 542–550

    Article  CAS  PubMed  Google Scholar 

  27. Zhang LH et al. Intrasplenic transplantation of IL-18 gene-modified hepatocytes: an effective approach to reverse hepatic fibrosis in schistosomiasis through induction of dominant Th1 response Gene Therapy 2001 8: 1333–1342

    Article  CAS  PubMed  Google Scholar 

  28. Wen D et al. Interleukin 18 transfection enhances antitumor immunity induced by dendritic cell-tumor cell conjugates Cancer Res 2001 61: 3735–3740

    Google Scholar 

  29. Ghivizzani SC et al. Constitutive intra-articular expression of human IL-1 beta following gene transfer to rabbit synovium produces all major pathologies of human rheumatoid arthritis J Immunol 1997 159: 3604–3612

    CAS  PubMed  Google Scholar 

  30. Hardy S et al. Construction of adenovirus vectors through Cre-lox recombination J Virol 1997 71: 1842–1849

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Cormack BP, Valdiva RH, Falkow S . FACS-optimized mutants of the green fluorescent protein (GFP) Gene 1996 177: 33–38

    Article  Google Scholar 

  32. Nishioka Y et al. Induction of systemic and therapeutic antitumor immunity using intratumoral injection of dendritic cells genetically modified to express Interleukin-12 Cancer Res 1999 59: 4035–4041

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by Grant PO1 CA59371 (to MTL, PDR and HT), by The Uehara Memorial Foundation (Tokyo, Japan) Postdoctoral Research Fellowship (to FT), and by Grant-in Aid for Scientific Research (B: 12470237) from Japan Society for the Promotion of Science (to HT). We thank Susan F Schoonover (University of Pittsburgh) for her excellent technical assistance. We are grateful to Drs Andrea Gambotto, Tadashi Osaki (University of Pittsburgh) for generating adenoviral vector, and Dr Takuya Takayama, Motohiro Hirao (University of Pittsburgh) for helpful discussion. We also thank Professor Masaki Mori (Kyushu University, Japan) for helpful suggestions.

Author information

Author notes

  1. F Tanaka

    Present address: Division of Molecular and Surgical Oncology, Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu, 874-0838, Japan

Authors and Affiliations

  1. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    F Tanaka, W Hashimoto, M T Lotze & H Tahara

  2. Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    F Tanaka, W Hashimoto, P D Robbins, M T Lotze & H Tahara

  3. Department of Surgery and Bioengineering, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    H Tahara

Authors
  1. F Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P D Robbins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M T Lotze
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Tahara
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tanaka, F., Hashimoto, W., Robbins, P. et al. Therapeutic and specific antitumor immunity induced by co-administration of immature dendritic cells and adenoviral vector expressing biologically active IL-18. Gene Ther 9, 1480–1486 (2002). https://doi.org/10.1038/sj.gt.3301827

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301827

Keywords

This article is cited by

Search

Advanced search

Quick links