Hepatocellular carcinoma cell sensitivity to Vγ9Vδ2 T lymphocyte-mediated killing is increased by zoledronate

Shiori Sugai, Toshiaki Yoshikawa, Tatsuaki Iwama, Nobuhiro Tsuchiya, Norihiro Ueda, Norihiro Fujinami, Manami Shimomura, Rong Zhang, Shin Kaneko, Yasushi Uemura, Tetsuya Nakatsura

Research output: Contribution to journalArticlepeer-review


The limited efficacy of vaccines in hepatocellular carcinoma (HCC), due to the low frequency of tumor-infiltrating cytotoxic T lymphocytes (CTLs), indicates the importance of innate immune surveillance, which assists acquired immunity by directly recognizing and eliminating HCC. Innate Vγ9Vδ2 T cells have major histocompatibility complex-unrestricted antitumor activity and are activated by phosphoantigens, which are upregulated in cancer cells by the nitrogen-containing bisphosphonate, zoledronate (Zol). A better understanding of HCC susceptibility to Zol and downstream γδ T cell-mediated killing is essential to optimize γδ T cell-mediated immunotherapy. This study systematically examined the interactions between γδ T cells and Zol-treated HCC cell lines (HepG2, HLE, HLF, HuH-1, JHH5, JHH7, and Li-7) in vitro. All HCC cell lines expressed the DNAX accessory molecule-1 ligands, poliovirus receptor, and Nectin-2, and γδ T cell-mediated k illing of t hese c ells was significantly enhanced by Zol. Small interfering RNA-mediated knockdown of these ligands did not affect the susceptibility to γδ T cell lysis. This killing activity was partly inhibited by mevastatin, an inhibitor of the mevalonate pathway, and markedly reduced by a monoclonal antibody to γ- and δ-chain T cell receptor, indicating that this is crucial for Zol-induced HCC k illing. I n addition, Z ol-treated HCC cell l ines t riggered γδ T cell proliferation and induced production of Th1 and Th2, but not Th17, cytokines. The Zol concentration that enhanced HCC cell susceptibility to γδ T cell k illing was lower than that required to directly inhibit HCC proliferation. Thus, γδ T cells may be important effector cells in the presence of Zol, especially where there are insufficient number of cancer antigen-specific CTLs to eliminate HCC. Our in vitro data support the proposal that Zol-treatment, combined with adaptive γδ T cell immunotherapy, may provide a feasible and effective approach for treatment of HCC.

Original languageEnglish
Pages (from-to)1794-1804
Number of pages11
JournalInternational journal of oncology
Issue number5
Publication statusPublished - 2016 May
Externally publishedYes


  • Cancer immunotherapy
  • Hepatocellular carcinoma
  • Isopentenyl pyrophosphate
  • Zoledronate
  • γδ T cell

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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