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Adenovirus-mediated interleukin-18 mutant in vivo gene transfer inhibits tumor growth through the induction of T cell immunity and activation of natural killer cell cytotoxicity

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Abstract

We report here that gene transfer using recombinant adenoviruses encoding interleukin (IL)-18 mutants induces potent antitumor activity in vivo. The precursor form of IL-18 (ProIL-18) is processed by caspase-1 to produce bioactive IL-18, but its cleavage by caspase-3 (CPP32) produces an inactive form. To prepare IL-18 molecules with an effective antitumor activity, a murine IL-18 mutant with the signal sequence of murine granulocyte-macrophage (GM)- colony stimulating factor (CSF) at the 5′-end of mature IL-18 cDNA (GMmIL-18) and human IL-18 mutant with the prepro leader sequence of trypsin (PPT), which is not cleaved by caspase-3 (PPThIL-18CPP32−), respectively, were constructed. Adenovirus vectors carrying GMmIL-18 or PPThIL-18CPP32− produced bioactive IL-18. Ad.GMmIL-18 had a more potent antitumor effect than Ad.mProIL-18 encoding immature IL-18 in renal cell adenocarcinoma (Renca) tumor-bearing mice. Tumor-specific cytotoxic T lymphocytes, the induction of Th1 cytokines, and an augmented natural killer (NK) cell activity were detected in Renca tumor-bearing mice treated with Ad.GMmIL-18. An immunohistological analysis revealed that CD4+ and CD8+ T cells abundantly infiltrated into tumors of mice treated with Ad.GMmIL-18. Huh-7 human hepatoma tumor growth in nude mice with a defect of T cell function was significantly inhibited by Ad.PPThIL-18CPP32− compared with Ad.hProIL-18 encoding immature IL-18. Nude mice treated with Ad.PPThIL-18CPP32− contained NK cells with increased cytotoxicity. The results suggest that the release of mature IL-18 in tumors is required for achieving an antitumor effect including tumor-specific cellular immunity and augmented NK cell-mediated cytotoxicity. These optimally designed IL-18 mutants could be useful for improving the antitumor effectiveness of wild-type IL-18.

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Acknowledgements

We thank Sanghyeon Kim for cloning of IL-18 cDNAs, and JS Lim and KD Kim for immunological assays.

This work was supported by a Grant (FG03-32-02) of 21C Frontier Functional Genome Project from the Ministry of Science and Technology, South Korea.

Kyung-Sun Hwang and Won-Kyung Cho have contributed equally to this work.

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Authors and Affiliations

  1. Cell Biology Laboratory/Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Republic of Korea

    Kyung-Sun Hwang, Won-Kyung Cho, Jinsang Yoo & Dong-Soo Im

  2. Samyang Genex Biotech Research Institute, Daejeon, Republic of Korea

    Young Rim Seong

  3. Department of Pathology, College of Medicine, Konyang University, Daejeon, Republic of Korea

    Bum-Kyeng Kim

  4. Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea

    Samyong Kim

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  1. Kyung-Sun Hwang
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Correspondence to Dong-Soo Im.

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Hwang, KS., Cho, WK., Yoo, J. et al. Adenovirus-mediated interleukin-18 mutant in vivo gene transfer inhibits tumor growth through the induction of T cell immunity and activation of natural killer cell cytotoxicity. Cancer Gene Ther 11, 397–407 (2004). https://doi.org/10.1038/sj.cgt.7700711

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  • DOI: https://doi.org/10.1038/sj.cgt.7700711

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