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Gene transfer of CD40-ligand to dendritic cells stimulates interferon-γ production to induce growth arrest and apoptosis of tumor cells

Gene Therapy volume 15, pages 203–213 (2008)Cite this article

Abstract

In this study, we present evidence that gene transfer of the CD40-ligand (CD154) into human immature dendritic cells (DC) imparts direct antitumor effects on tumor cells. DC infected with adenovirus directed to express human CD154 on the cell surface (CD154-DC) elicited significantly higher levels of immune accessory molecules commonly found on mature DC. We found that co-cultivation with a human squamous cell carcinoma cell line (OSC-70) with CD154-DC significantly inhibited cell growth. We further demonstrate that OSC-70 cells stimulated with CD154-DC were more susceptible to apoptosis via TNF-related apoptosis inducing ligand (TRAIL). Importantly, tumor cells co-cultured with CD154-DC in transwell plates expressed upregulated cell surface TRAIL-R2. CD154-DC produced higher levels of interferon (IFN)-γ, IL-12p70 and soluble CD154, but the ability of CD154-DC to inhibit tumor cell growth was significantly abrogated by a neutralizing antibody to IFN-γ, indicating that this was mainly mediated by IFN-γ. Furthermore, intratumoral injection of CD154-DC significantly suppressed OSC-70 tumor growth in a xenograft model. Overall, these results reveal that CD154-DC have potential as an anti-cancer therapy by producing IFN-γ to arrest adjacent tumor cell growth and increase the susceptibility of apoptosis via TRAIL.

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Acknowledgements

We thank Hokkaido Red Cross Blood Center for providing us with human peripheral blood, and Tomoko Sonoda for her analysis assistance.This work was supported by Grant-in-Aid for Scientific Research on Priority Areas ‘Cancer’ from the Ministry of Education, Culture, Sports, Science and Technology (K Kato, K Nakamura and H Hamada) and by Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan (H Hamada) and by Grant-in-Aid from Japan Leukemia Research Fund (K Kato).

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Authors and Affiliations

  1. Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

    K Tomihara, K Kato, Y Masuta, K Nakamura, H Uchida, K Sasaki, T Tanaka, J Huang & H Hamada

  2. Department of Oral Surgery, Sapporo Medical University, Sapporo, Japan

    K Tomihara & H Hiratsuka

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Correspondence to K Kato.

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Tomihara, K., Kato, K., Masuta, Y. et al. Gene transfer of CD40-ligand to dendritic cells stimulates interferon-γ production to induce growth arrest and apoptosis of tumor cells. Gene Ther 15, 203–213 (2008). https://doi.org/10.1038/sj.gt.3303056

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