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Treatment of hepatocellular carcinoma with adenoviral vector-mediated Flt3 ligand gene therapy

Cancer Gene Therapy volume 12, pages 769–777 (2005)Cite this article

Abstract

Fms-like tyrosine kinase 3 ligand (Flt3L) plays an important role in development and activation of dendritic cells (DCs) and natural killer cells (NK). It has been shown that administration of either tumor cells transfected in vitro with Flt3L vectors or soluble Flt3L fusion protein in a high dose can enhance host antitumor immunity in animal model systems. In this study, we developed a recombinant defective adenovirus with an insert of gene encoding extracellular domain of mouse Flt3L (Ad-mFlt3L) under control of cytomegalovirus promoter and investigated its biological efficacy in eliciting tumor-specific immune response against hepatocellular carcinoma in mouse hepatoma model. The constructed Ad-mFlt3L efficiently infected hepa 1–6 hepatoma cells both in vitro and in vivo, leading to a high production of mFlt3L proteins in association with accumulation of DCsNK cells and lymphocytes in local tumor tissues. Tumor cells infected with Ad-mFlt3L lost tumorigenicity and became more immunogenic in syngeniec animal models. Intratumoral injection of Ad-mFlt3L (109 expression-forming unit) × 3 significantly inhibited tumor growth with elicitation of long-lasting antitumor immunity, which is both preventive and curative. The tumor-specific immunity can be partially abrogated by depletion of either CD3+CD4+ T cells or NK cells and can be also re-established in naïve animals by adoptive transfer of splenocytes from treated mice. The results suggest that adenovirus-mediated Flt3L gene therapy may provide a useful strategy for treatment of cancers.

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Abbreviations

CMV:

cytomegalovirus

DMEM:

minimal essential medium

FBS:

fetal bovine serum

efu:

expression-forming unit

MOI:

multiplicity of infection

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NK:

natural killer

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Acknowledgements

This work was supported in part by the grants from National Natural Science Foundation of China, Shanghai Commission of Science and Technology and Ministry of Science and Technology of China as well as a special grant from Shanghai Pudong Bureau of Science and Technology of China.

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Author notes

  1. Hao Wang, Jianxin Dai and Sheng Hou: These authors contributed equally to this paper.

Authors and Affiliations

  1. International Joint Cancer Institute and E-institutes of Shanghai Universities Immunology Division, The Second Military Medical University, Shanghai, 200433, People's Republic of China

    Hao Wang, Jianxin Dai, Sheng Hou, Weizhu Qian, Bohua Li, Jing Ma, Xiaoqiang Fan, Jian Zhao, Shilin Yang, Hongxun Sang, Qing Yang, Rongfu Wang & Yajun Guo

  2. Eppley Cancer Institute and Department of Pathology and Microbiology, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, 68198, Nebraska, USA

    Jianxin Dai, Jing Ma, Shilin Yang, Hongxun Sang & Yajun Guo

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  1. Hao Wang
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  2. Jianxin Dai
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Correspondence to Yajun Guo.

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Wang, H., Dai, J., Hou, S. et al. Treatment of hepatocellular carcinoma with adenoviral vector-mediated Flt3 ligand gene therapy. Cancer Gene Ther 12, 769–777 (2005). https://doi.org/10.1038/sj.cgt.7700843

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