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Eradication of hepatoma and colon cancer in mice with Flt3L gene therapy in combination with 5-FU

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Abstract

We developed a recombinant defective adenovirus with an insert of gene encoding extracellular domain of mouse Flt3L (Ad-mFlt3L) under control of cytomegalovirus promoter to investigate the biological efficacy of Flt3L in combination with chemotherapeutical drug, 5-FU, in eliciting an effective anti-cancer immunity in mouse hepatoma and colon cancer model systems. The constructed Ad-mFlt3L efficiently infected hepatoma and colon cancer cells both in vitro and in vivo, leading to a high production of mFlt3L proteins in association with accumulation of DCs, NK cells and lymphocytes in local tumor tissues. Administration of Ad-mFlt3L can protect bone marrow injury caused by 5-Fu and stimulates proliferation and maturation of lymphocytes, APCs and NKs. Intratumoral injection of Ad-mFlt3L followed by an intraperitoneal administration of 5-Fu significantly inhibited tumor growth and cured established tumors. Adenovirus mediated Flt3L gene therapy synergies with chemotherapeutic drug, 5-Fu, in elicitation of long-lasting antitumor immunity. The tumor specific immunity can be adoptively transferred into naïve animals successfully by transfusion of CD3+CD8+ T cells from the treated mice. The data suggests that adenovirus mediated Flt3L gene therapy in combination with 5-Fu chemotherapy may open a new avenue for development of anti-cancer chemogenetherapy.

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Abbreviations

Flt3L:

Fms-like tyrosine kinase 3 ligand

NK:

Natural killer

HCC:

Hepatocellular carcinoma

5-Fu:

5-Fluorouracil

MEM:

Minimal essential medium

Ad-mFL:

Adenovirus with an insert of gene encoding extracellular domain of mouse Flt3L

MTT:

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

FBS:

Fetal bovine serum

CMV:

Cytomegalovirus

EFU:

Expression-forming unit

CFU:

Colony-forming unit

BFU:

Burst-forming unit

MOI:

Multiplicity of infection

IHC:

Immunohistochemistry

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Acknowledgments

This work was supported in part by the grants from National Natural Science Foundation of China, Shanghai Commission of Science and Technology, E-Institutes of Shanghai Universities Immunology Division and Ministry of Science and Technology of China (973 and 863 projects) as well as a special grant from Shanghai Pudong Bureau of Science and Technology of China.

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Authors and Affiliations

  1. International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433, People’s Republic of China

    Sheng Hou, Geng Kou, Xiaoqiang Fan, Hao Wang, Weizhu Qian, Dapeng Zhang, Bohua Li, Jianxin Dai, Jian Zhao, Jing Ma, Jing Li, Mengchao Wu & Yajun Guo

  2. Shanghai Center for Cell Engineering and Antibody, Research Building, 399 Libing Road, Shanghai, 201203, People’s Republic of China

    Sheng Hou, Geng Kou, Hao Wang, Weizhu Qian, Bohua Li, Jing Li, Birong Lin & Yajun Guo

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  1. Sheng Hou
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  2. Geng Kou
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  3. Xiaoqiang Fan
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  4. Hao Wang
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  5. Weizhu Qian
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  7. Bohua Li
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  8. Jianxin Dai
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  9. Jian Zhao
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  11. Jing Li
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  12. Birong Lin
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  13. Mengchao Wu
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  14. Yajun Guo
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Corresponding author

Correspondence to Yajun Guo.

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Sheng Hou, Geng Kou, and Xiaoqiang Fan are contribute equally to this paper.

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Hou, S., Kou, G., Fan, X. et al. Eradication of hepatoma and colon cancer in mice with Flt3L gene therapy in combination with 5-FU. Cancer Immunol Immunother 56, 1605–1613 (2007). https://doi.org/10.1007/s00262-007-0306-3

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  • DOI: https://doi.org/10.1007/s00262-007-0306-3

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