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Virus-mediated oncolysis induces danger signal and stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation

Oncogene volume 27, pages 2375–2381 (2008)Cite this article

Abstract

Dendritic cells (DCs) are the most potent antigen-presenting cells and acquire cellular antigens and danger signals from dying cells to initiate antitumor immune responses via direct cell-to-cell interaction and cytokine production. The optimal forms of tumor cell death for priming DCs for the release of danger signals are not fully understood. OBP-301 (Telomelysin) is a telomerase-specific replication-competent adenovirus that induces selective E1 expression and exclusively kills human cancer cells. Here, we show that OBP-301 replication produced the endogenous danger signaling molecule, uric acid, in infected human tumor cells, which in turn stimulated DCs to produce interferon-γ (IFN-γ) and interleukin 12 (IL-12). Subsequently, IFN-γ release upregulated the endogenous expression of the proteasome activator PA28 in tumor cells and resulted in the induction of cytotoxic T-lymphocytes. Our data suggest that virus-mediated oncolysis might be the effective stimulus for immature DCs to induce specific activity against human cancer cells.

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Acknowledgements

We thank Drs Tamotsu Yoshimori and Frank McCormick for providing pLC3-GFP plasmid and Onyx-015, respectively.

The study was supported by Grants-in-Aid from the Ministry of Education, Science and Culture, Japan; and Grants from the Ministry of Health and Welfare, Japan.

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Authors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Y Endo, R Sakai, M Hioki, S Kagawa, F Uno, N Tanaka & T Fujiwara

  2. Center for Gene and Cell Therapy, Okayama University Hospital, Okayama, Japan

    Y Endo, R Sakai, M Hioki, S Kagawa, F Uno & T Fujiwara

  3. Oncolys BioPharma Inc., Tokyo, Japan

    M Ouchi, H Onimatsu, Y Watanabe & Y Urata

Authors
  1. Y Endo
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  2. R Sakai
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  3. M Ouchi
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  4. H Onimatsu
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  5. M Hioki
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  6. S Kagawa
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  9. Y Urata
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  10. N Tanaka
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  11. T Fujiwara
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Corresponding author

Correspondence to T Fujiwara.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Endo, Y., Sakai, R., Ouchi, M. et al. Virus-mediated oncolysis induces danger signal and stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation. Oncogene 27, 2375–2381 (2008). https://doi.org/10.1038/sj.onc.1210884

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