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Triple expression of B7-1, B7-2 and 4-1BBL enhanced antitumor immune response against mouse H22 hepatocellular carcinoma

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Abstract

Objectives

Costimulatory signals are essential for T-cell activation and hence play a very important role in antitumor immunity. B7 and 4-1BBL which belongs to tumor necrosis factor (TNF) family provide costimulatory interaction for T-cell activation and function. This study investigated the role of B7 and 4-1BBL in the amplification of tumor immunity by transduction of the B7-1, B7-2 and 4-1BBL into mouse hepatocellular carcinoma cell line H22.

Methods

The tumorigenicity of H22 variants expressing either B7-1, B7-2 (H22/B7-1/B7-2) or 4-1BBL was compared with an H22 variant expressing B7-1, B7-2 and 4-1BBL (H22/B7-1/B7-2/4-1BBL). The study next investigated whether the combination of B7-1/B7-2 and 4-1BBL cell injection induced cytotoxic T lymphocyte (CTL) response and IL-2/IFN-γ secretion. The immune mechanisms underlying this combination treatment were then analyzed.

Results

Syngeneic BALB/c mice injected with H22/B7-1/B7-2/4-1BBL cells that expressed elevated levels of B7-1, B7-2 and 4-1BBL showed a tumor development frequency of 50% compared with 100% in mice injected with the H22 parental line, H22/neo, H22/B7-1/B7-2 and H22/4-1BBL. Mice inoculated with H22 tumor cells expressing B7-1, B7-2 and 4-1BBL developed a strong cytotoxic T lymphocyte response and long-term immunity against wild-type tumor, suggesting a synergistic effect between the B7 and 4-1BBL costimulatory pathways. Results showed that H22/B7-1/B7-2/4-1BBL tumor vaccines probably protect the infiltrating lymphocytes from apoptosis and induce NF-κB activation to improve T-cell-mediated antitumor response.

Conclusions

In this study, the antitumor consequences of using B7-1, B7-2 and 4-1BBL gene transfer have demonstrated the therapeutic potential of gene therapy approach for hepatocellular carcinoma.

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Acknowledgments

This work was funded in part by National Natural Science Foundation of China (No. 30901442); Natural Science Foundation of Jiansu Province (No. BK2009439); and Open Foundation from Health Department, Jiangsu Province (No. ZX05 200901).

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Authors and Affiliations

  1. Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China

    Guoqiang Li, Xiaofeng Wu, Feng Zhang, Xiangcheng Li, Beicheng Sun, Yue Yu, Aihong Yin, Lei Deng & Xuehao Wang

  2. Department of Respiratory Medicine, Jinling Hospital, 305 Zhongshan East Road, Nanjing, 210002, China

    Jie Yin

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  1. Guoqiang Li
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  2. Xiaofeng Wu
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  3. Feng Zhang
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  4. Xiangcheng Li
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  5. Beicheng Sun
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  6. Yue Yu
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  7. Aihong Yin
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  9. Jie Yin
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  10. Xuehao Wang
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Correspondence to Jie Yin or Xuehao Wang.

Additional information

Guoqiang Li and Xiaofeng Wu contributed equally to this work.

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Li, G., Wu, X., Zhang, F. et al. Triple expression of B7-1, B7-2 and 4-1BBL enhanced antitumor immune response against mouse H22 hepatocellular carcinoma. J Cancer Res Clin Oncol 137, 695–703 (2011). https://doi.org/10.1007/s00432-010-0905-9

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  • DOI: https://doi.org/10.1007/s00432-010-0905-9

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