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T-cell-dependent antitumor effects produced by CD40 ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines

Cancer Gene Therapy volume 10, pages 451–456 (2003)Cite this article

Abstract

CD40/CD40 ligand (CD40L) interaction plays an essential role in cell-mediated immune responses. We examined whether expression of CD40L in murine lung carcinoma (A11) cells could produce antitumor effects. The proliferation rate in vitro of A11 cells transfected with the murine CD40L gene (A11/CD40L) was not different from that of parent cells; however, half of the immunocompetent mice inoculated with A11/CD40L cells did not form tumors and the growth of A11/CD40L tumors developed in the rest of mice was significantly retarded compared with that of parent tumors. Protective immunity was also induced in the mice that had rejected A11/CD40L cells. In T-cell-defective nude mice, these antitumor effects were not observed. Bone-marrow-derived dendritic cells (DCs), when cultured with A11/CD40L cells, formed clusters with the tumors and showed upregulated CD86 expression. Expression of the interleukin-23 (IL-23) p19, IL-12p35, IL-18, interferon-γ (IFN-γ) and Mig (monokine induced by IFN-γ) genes was induced in the DCs that were cultured with A11/CD40L but not with A11 cells, and P40, the subunit of both IL-12 and IL-23, was secreted from the cocultured DCs. These data directly showed that the expression of CD40L in tumors facilitated the interaction between DCs and the tumors, enhanced the maturation of DCs, induced secretion of cytokines, and consequently produced T-cell-dependent systemic immunity.

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References

  1. Cella M, Scheidegger D, Palmer-Lehmann K, et al. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med. 1996;184:747–752.

    Article  CAS  Google Scholar 

  2. Peng X, Kasran A, Warmerdam PA, et al. Accessory signaling by CD40 for T cell activation: induction of Th1 and Th2 cytokines and synergy with interleukin-12 for interferon-γ production. Eur J Immunol. 1996;26:1621–1627.

    Article  CAS  Google Scholar 

  3. Yang Y, Wilson JM . CD40 ligand-dependent T cell activation: requirement of B7-CD28 signaling through CD40. Science. 1996;273:1862–1864.

    Article  CAS  Google Scholar 

  4. Grewal IS, Flavell RA . The role of CD40 ligand in costimulation and T-cell activation. Immunol Rev. 1996;153:85–106.

    Article  CAS  Google Scholar 

  5. Mackey MF, Gunn JR, Ting PP, et al. Protective immunity induced by tumor vaccines requires interaction between CD40 and its ligand, CD154. Cancer Res. 1997;57:2569–2574.

    CAS  PubMed  Google Scholar 

  6. Kikuchi T, Crystal RG . Anti-tumor immunity induced by in vivo adenovirus vector-mediated expression of CD40 ligand in tumor cells. Hum Gene Ther. 1999;10:1375–1387.

    Article  CAS  Google Scholar 

  7. Noguchi M, Imaizumi K, Kawabe T, et al. Induction of antitumor immunity by transduction of CD40 ligand gene and interferon-γ gene into lung cancer. Cancer Gene Ther. 2001;8:421–429.

    Article  CAS  Google Scholar 

  8. Wierda WG, Cantwell MJ, Woods SJ, et al. CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia. Blood. 2000;96:2917–2924.

    CAS  Google Scholar 

  9. Kikuchi T, Moore MAS, Crystal RG . Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors. Blood. 2000;96:91–99.

    CAS  Google Scholar 

  10. Liu Y, Zhang X, Zhang W, et al. Adenovirus-mediated CD40 ligand gene-engineered dendritic cells elicit enhanced CD8+ cytotoxic T-cell activation and antitumor immunity. Cancer Gene Ther. 2002;9:202–208.

    Article  CAS  Google Scholar 

  11. Korst RJ, Mahtabifard A, Yamada R, Crystal RG . Effect of adenovirus gene transfer vectors on the immunologic functions of mouse dendritic cells. Mol Ther. 2002;5:307–315.

    Article  CAS  Google Scholar 

  12. Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13:715–725.

    Article  CAS  Google Scholar 

  13. Takasu M, Tada Y, Wang JO, Tagawa M, Takenaga K . Resistance to apoptosis induced by microenvironmental stresses is correlated with metastatic potential in Lewis lung carcinoma. Clin Exp Metastasis. 1999;17:409–416.

    Article  CAS  Google Scholar 

  14. Tada Y, O-Wang J, Takiguchi Y, et al. A novel role for Fas ligand in facilitating antigen acquisition by dendritic cells. J Immunol. 2002;169:2241–2245.

    Article  CAS  Google Scholar 

  15. Rescigno M, Piguet V, Valzasina B, et al. Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1β, and the production of interferon γ in the absence of IL-12 during DC-T cell cognate interaction: a new role for Fas ligand in inflammatory responses. J Exp Med. 2000;192:1661–1668.

    Article  CAS  Google Scholar 

  16. Gardella S, Andrei C, Costigliolo S, et al. Interleukin-18 synthesis and secretion by dendritic cells are modulated by interaction with antigen-specific T cells. J Leukoc Biol. 1999;66:237–241.

    Article  CAS  Google Scholar 

  17. Stober D, Schirmbeck R, Reimann J . IL-12/IL-18-dependent IFN-γ release by murine dendritic cells. J Immunol. 2001;167:957–965.

    Article  CAS  Google Scholar 

  18. Morelli AE, Zahorchak AF, Larregina AT, et al. Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation. Blood. 2001;98:1512–1523.

    Article  CAS  Google Scholar 

  19. Padovan E, Spagnoli GC, Ferrantini M, Heberer M . IFN-α2a induces IP-10/CXCL10 and MIG/CXCL9 production in monocyte-derived dendritic cells and enhances their capacity to attract and stimulate CD8+ effector T cells. J Leukoc Biol. 2002;71:669–676.

    CAS  PubMed  Google Scholar 

  20. Wong P, Severns CW, Guyer NB, Wright TM . A unique palindromic element mediates gamma interferon induction of mig gene expression. Mol Cell Biol. 1994;14:914–922.

    Article  CAS  Google Scholar 

  21. Kuniyoshi JS, Kuniyoshi CJ, Lim AM, et al. Dendritic cell secretion of IL-15 is induced by recombinant huCD40LT and augments the stimulation of antigen-specific cytolytic T cells. Cell Immunol. 1999;193:48–58.

    Article  CAS  Google Scholar 

  22. Parrish-Novak J, Dillon SR, Nelson A, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408:57–63.

    Article  CAS  Google Scholar 

  23. Kasaian MT, Whitters MJ, Carter LL, et al. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity. 2002;16:559–569.

    Article  CAS  Google Scholar 

  24. Batrla R, Linnebacher M, Rudy W, et al. CD40-expressing carcinoma cells induce down-regulation of CD40 ligand (CD154) and impair T-cell functions. Cancer Res. 2002;62:2052–2057.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (JSPS). L Yu and Y-Q Wang were supported by the JSPS postdoctoral fellowship.

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Authors and Affiliations

  1. Division of Pathology, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, 260-8717, Chiba, Japan

    Yuji Tada, Jiyang O-Wang, Ling Yu, Osamu Shimozato, Yan-Qing Wang, Shigeru Sakiyama & Masatoshi Tagawa

  2. Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, 260-8670, Chiba, Japan

    Yuji Tada, Yuichi Takiguchi, Koichiro Tatsumi & Takayuki Kuriyama

  3. Division of Chemotherapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717, Japan

    Keizo Takenaga

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Correspondence to Masatoshi Tagawa.

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Tada, Y., O-Wang, J., Yu, L. et al. T-cell-dependent antitumor effects produced by CD40 ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines. Cancer Gene Ther 10, 451–456 (2003). https://doi.org/10.1038/sj.cgt.7700584

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