| RRC ID |
79446
|
| Author |
Nishio N, Fujita M, Tanaka Y, Maki H, Zhang R, Hirosawa T, Demachi-Okamura A, Uemura Y, Taguchi O, Takahashi Y, Kojima S, Kuzushima K.
|
| Title |
Zoledronate sensitizes neuroblastoma-derived tumor-initiating cells to cytolysis mediated by human γδ T cells.
|
| Journal |
J Immunother
|
| 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.
|
| Volume |
35(8)
|
| Pages |
598-606
|
| Published |
2012-10-1
|
| DOI |
10.1097/CJI.0b013e31826a745a
|
| PII |
00002371-201210000-00002
|
| PMID |
22996365
|
| MeSH |
Adolescent
Adult
Animals
Antineoplastic Agents / administration & dosage*
Bone Marrow Neoplasms / immunology
Bone Marrow Neoplasms / pathology
Bone Marrow Neoplasms / therapy*
Cell Line, Tumor
Child
Cytotoxicity, Immunologic / drug effects
Diphosphonates / administration & dosage*
Drug Synergism
Female
Growth Inhibitors / administration & dosage*
Humans
Imidazoles / administration & dosage*
Immunotherapy, Adoptive / methods*
Interleukin-15 / pharmacology
Interleukin-18 / pharmacology
Male
Mice
Mice, SCID
Neoplastic Stem Cells / drug effects*
Neoplastic Stem Cells / immunology
Neoplastic Stem Cells / pathology
Neuroblastoma / immunology
Neuroblastoma / pathology
Neuroblastoma / therapy*
Receptors, Antigen, T-Cell, gamma-delta / immunology
T-Lymphocytes / drug effects*
T-Lymphocytes / immunology
T-Lymphocytes / transplantation
Xenograft Model Antitumor Assays
Young Adult
Zoledronic Acid
|
| IF |
4.11
|
| Resource |
| Human and Animal Cells |
NB-1(RCB1953)
NB9(RCB0477)
NB19(RCB0479)
CHP-134(RCB0487) |
