Zoledronate Sensitizes Neuroblastoma-derived Tumor-initiating Cells to Cytolysis Mediated by Human γδ T Cells
| Autor: | Nobuhiro Nishio, Mitsugu Fujita, Seiji Kojima, Yoshimasa Tanaka, Osamu Taguchi, Yoshiyuki Takahashi, Tomoya Hirosawa, Ayako Demachi-Okamura, Kiyotaka Kuzushima, Yasushi Uemura, Hiroyuki Maki, Rong Zhang |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Adult
Cytotoxicity Immunologic Male Cancer Research Adolescent T-Lymphocytes medicine.medical_treatment T cell Immunology Population Antineoplastic Agents Mice SCID Immunotherapy Adoptive Zoledronic Acid Mice Neuroblastoma Young Adult Antigen Cell Line Tumor medicine Animals Humans Immunology and Allergy Child education Interleukin-15 Pharmacology education.field_of_study Diphosphonates Chemistry Imidazoles Interleukin-18 Drug Synergism Receptors Antigen T-Cell gamma-delta Immunotherapy medicine.disease Xenograft Model Antitumor Assays Growth Inhibitors Cytolysis medicine.anatomical_structure Cell culture Neoplastic Stem Cells Cancer research Female Bone Marrow Neoplasms Ex vivo |
| Zdroj: | Journal of Immunotherapy. 35:598-606 |
| ISSN: | 1524-9557 |
| DOI: | 10.1097/cji.0b013e31826a745a |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|