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Augmentation of local antitumor immunity in liver by interleukin-2 gene transfer via portal vein

Cancer Gene Therapy volume 9, pages 655–664 (2002)Cite this article

Abstract

Metastasis to the liver remains an important problem in the treatment of patients with gastrointestinal cancer. We examined the mechanism and effect on liver metastasis of in vivo interleukin-2 (IL-2) gene transfer to the liver. RCN-9 cells derived from F344 rat colon adenocarcinoma were injected into syngeneic rats via the ileocecal vein to induce liver tumors. A total of 2.5×109 pfu of adenovirus vector harboring the human IL-2 gene (AdCMVhIL-2), or 2.5×109 pfu of control vector encoding β-galactosidase was administered before RCN-9 cell challenge. On day 14, mean tumor weight was 4.0±2.4 g in the control group, whereas IL-2–transduced livers had no tumors. Survival of AdCMVhIL-2–treated rats was significantly longer than that of control rats (P<.01). Flow cytometry demonstrated that the proportion of natural killer (NK) cells had increased among sinusoidal cells collected from IL-2–transduced livers. These cells were highly cytotoxic to RCN-9 cells in vitro in the presence of a physiological high concentration of recombinant IL-2. Preventative effects of IL-2 transduction of the liver against liver metastasis were lost after depletion of NK cells by treatment with anti–asialo GM1 antibodies. Our results indicate that IL-2 gene transfer to the liver prevents liver metastasis by continuously providing physiological high concentrations of IL-2 in the liver, thereby activating sinusoidal NK cells.

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Acknowledgements

We thank Atsushi Miyanohara, University of California, San Diego, Program in Human Gene Therapy, for preparation of adenovirus vectors. We are also grateful to Yuko Ishida and Yasuko Kimura for excellent technical assistance. This work was supported, in part, by Grants-in-Aid from the Ministry of Education, Science and Culture, Japan, and by a grant from the Tsuchiya Foundation.

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Authors and Affiliations

  1. Department of Surgery II, Faculty of Medicine, Hiroshima University, Hiroshima, Japan

    Hidehiro Tanji, Hiroshi Yahata, Keisuke Hayamizu, Katsunori Shinozaki, Tatsuya Okimoto & Toshimasa Asahara

  2. Department of Bacteriology, Faculty of Medicine, Hiroshima University, Hiroshima, Japan

    Takemasa Sakaguchi

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  1. Hidehiro Tanji
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  2. Hiroshi Yahata
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Correspondence to Hiroshi Yahata.

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Tanji, H., Yahata, H., Hayamizu, K. et al. Augmentation of local antitumor immunity in liver by interleukin-2 gene transfer via portal vein. Cancer Gene Ther 9, 655–664 (2002). https://doi.org/10.1038/sj.cgt.7700483

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