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NK Cells Are the Crucial Antitumor Mediators When STAT3-Mediated Immunosuppression Is Blocked in Hepatocellular Carcinoma

Qiangjun Sui, Jian Zhang, Xiaoxia Sun, Cai Zhang, Qiuju Han and Zhigang Tian
J Immunol August 15, 2014, 193 (4) 2016-2023; DOI: https://doi.org/10.4049/jimmunol.1302389
Qiangjun Sui
*Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China; and
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Jian Zhang
*Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China; and
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Xiaoxia Sun
*Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China; and
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Cai Zhang
*Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China; and
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Qiuju Han
*Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China; and
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Zhigang Tian
*Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China; and
†Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
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Abstract

STAT3 is highly activated in a wide variety of cancers and functions to promote tumor survival. We previously reported that blocking STAT3 activation inhibited human hepatocellular carcinoma (HCC) growth in vitro, but whether this treatment also triggered antitumor immune responses in vivo remained unknown. In this study, we found that blocking the STAT3 pathway in HCC cells dramatically inhibited murine HCC growth in vivo and prolonged survival of tumor-bearing mice. Importantly, the presence of STAT3-blocked HCC augmented NK cell cytotoxicity against HCC and increased expression of molecules associated with NK cell activation and cytotoxicity. In T cell–deficient nude mice, a unique NK cell–mediated antitumor function against STAT3-blocked HCC was suggested. NK cells were shown to be necessary and sufficient in NK or T cell depletion experiments, or by adoptively transferring NK cells. Furthermore, regulatory T cells and immunosuppressive IL-10 and TGF-β cytokines were reduced in mice bearing STAT3-blocked HCC cells, suggesting that these factors may be involved in HCC-induced NK cell suppression. These findings indicate that blocking STAT3 in HCC cells can initiate innate immunity in vivo.

Footnotes

  • This work was supported by National Basic Research Program of China Grant 2013CB531503, National Natural Science Foundation of China Grants 30628014 and 81172789, and National Mega Project on Major Infectious Diseases Prevention and Treatment Grant 2012ZX10002006.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    DC
    dendritic cell
    FasL
    Fas ligand
    HCC
    hepatocellular carcinoma
    ODN
    oligonucleotide
    Treg
    regulatory T cell
    VEGF
    vascular endothelial growth factor.

  • Received September 9, 2013.
  • Accepted June 10, 2014.
  • Copyright © 2014 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 193 (4)
The Journal of Immunology
Vol. 193, Issue 4
15 Aug 2014
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NK Cells Are the Crucial Antitumor Mediators When STAT3-Mediated Immunosuppression Is Blocked in Hepatocellular Carcinoma
Qiangjun Sui, Jian Zhang, Xiaoxia Sun, Cai Zhang, Qiuju Han, Zhigang Tian
The Journal of Immunology August 15, 2014, 193 (4) 2016-2023; DOI: 10.4049/jimmunol.1302389

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NK Cells Are the Crucial Antitumor Mediators When STAT3-Mediated Immunosuppression Is Blocked in Hepatocellular Carcinoma
Qiangjun Sui, Jian Zhang, Xiaoxia Sun, Cai Zhang, Qiuju Han, Zhigang Tian
The Journal of Immunology August 15, 2014, 193 (4) 2016-2023; DOI: 10.4049/jimmunol.1302389
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