title: Zoledronate sensitizes neuroblastoma-derived tumor-initiating cells to cytolysis mediated by human γδ T cells.
abstract: Neuroblastoma is the most common extracranial solid tumor in children that is refractory to intensive multimodal therapy. In particular, tumor-initiating cells (TICs) derived from neuroblastoma are believed responsible for tumor formation and resistance to the conventional therapy; an optimal strategy therefore should target this population. Technically, TICs can be enriched from neuroblastoma-derived spheres when the tumor cells are cultured in a serum-free medium supplemented with certain growth factors. Recently, a line of evidence has suggested antitumor potential of Vγ9Vδ2 T cells (γδ T cells), a T-cell population that recognizes and kills target cells independent of surface HLA expressions. Furthermore, a mevalonate pathway inhibitor, zoledronate, has been reported to enhance cytolytic activity of γδ T cells. On the basis of these findings, we hypothesized that zoledronate would sensitize neuroblastoma TICs to γδ T-cell-mediated cytolysis and promote therapeutic efficacy against neuroblastoma. In the current study, we show that zoledronate efficiently sensitizes both neuroblastoma-derived adherent cells and sphere-forming cells to γδ T-cell-mediated cytolysis. Subsequently, in vitro colony formation inhibition assay and in vivo animal studies reveal that the presence of γδ T cells decelerates outgrowth of neuroblastoma TICs. We finally show that addition of interleukin-15 and/or interleukin-18 in culture enhances the cytolytic activity of γδ T cells. On the basis of these data, we conclude that ex vivo expanded γδ T cells are a promising tool for antineuroblastoma immunotherapy with options for further improvement.
authors.affiliation: Division of Immunology, Aichi Cancer Center Research Institute, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishio
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Fujita
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Maki
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Tomoya
authors.initials: T
authors.lastname: Hirosawa
authors.forename: Ayako
authors.initials: A
authors.lastname: Demachi-Okamura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Uemura
authors.forename: Osamu
authors.initials: O
authors.lastname: Taguchi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kuzushima
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D019046:Bone Marrow Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002648:Child; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage*; D004357:Drug Synergism; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019409:Interleukin-15 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D009447:Neuroblastoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D006131:Growth Inhibitors; D007093:Imidazoles; D019409:Interleukin-15; D020382:Interleukin-18; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; D000077211:Zoledronic Acid