Membrane-bound interleukin-21 and CD137 ligand induce functional human natural killer cells from peripheral blood mononuclear cells through STAT-3 activation

Authors

  • X. Wang,

    1. Department of Pathology, College of Medicine, Yanbian University, Yanji, China
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  • D. A. Lee,

    1. Division of Pediatrics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
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  • Y. Wang,

    1. Department of Biochemistry and Molecular Cell Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
    2. Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai, China
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  • L. Wang,

    1. School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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  • Y. Yao,

    1. School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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  • Z. Lin,

    1. Department of Pathology, College of Medicine, Yanbian University, Yanji, China
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  • J. Cheng,

    1. Department of Biochemistry and Molecular Cell Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
    2. Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai, China
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  • S. Zhu

    Corresponding author
    1. Department of Biochemistry and Molecular Cell Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
    2. Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai, China
    • School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Correspondence: S. Zhu, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Shanghai 201203, China.

E-mail: jusco105@hotmail.com

Summary

Natural killer (NK) cell adoptive transfer is a promising approach for cancer immunotherapy; however, its development has been hindered by the lack of efficient methods to produce large numbers of functional NK cells. In this study, we engineered the leukaemia cell line K562 to express CD137 ligand (CD137L) and membrane-bound interleukin (mbIL)-21 on the cell surface, and used these cells to expand NK cells from the peripheral blood mononuclear cells. We found that purity of the NK cells (CD3CD56+/CD16+) increased from less than 30% to above 95% after a 3-week expansion and proliferation of the cells was sustained for more than 8 weeks. The surface expression of NK cell activating and inhibitory receptors, except for NKp80, was clearly increased with the expansion, and NK cell-mediated killing activity was also enhanced significantly. However, these changes in both phenotype and function were clearly reversed by JSI-124, a specific signal transducer and activator of transcription-3 (STAT-3) inhibitor. Taken together, data showed that the combination of mbIL-21 and CD137L could efficiently induce the formation of functional human NK cells from peripheral blood mononuclear cells, and STAT-3 inhibition could impair this induction. Therefore, STAT-3 activation may benefit human NK cell proliferation and cytotoxicity, and provide valuable clinical applications in NK cell immunotherapy against viral infectious diseases and cancers.

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