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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

Cancer Gene Therapy volume 11, pages 397–407 (2004)Cite this article

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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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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