title: Hepatocellular carcinoma cell sensitivity to Vγ9Vδ2 T lymphocyte-mediated killing is increased by zoledronate.
abstract: 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 killing of these cells 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 killing. In addition, Zol-treated HCC cell lines triggered 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 killing 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.
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Sugai
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Iwama
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tsuchiya
authors.affiliation: Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Ueda
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Fujinami
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Manami
authors.initials: M
authors.lastname: Shimomura
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Uemura
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakatsura
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects; D008113:Liver Neoplasms / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000077211:Zoledronic Acid
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid