The antitumour effect of {gamma}{delta} T-cells is enhanced by valproic acid-induced up-regulation of NKG2D ligands.
The aim of this study wsa to evaluate the additive effect of valproic acid (VPA) to γδ T-cell cytotoxicity against bladder cancer cells.


METHODS
Human bladder cancer cell lines TCCSUP and 253J were treated with VPA and mRNA expression of natural killer group 2D (NKG2D) ligands was determined. The antitumour effect of expanded γδ T-cells against zoledronic acid (ZOL) and VPA pre-treated cancer cells was subsequently determined.


RESULTS
VPA increased mRNA expression of NKG2D ligands on both cancer cell types. A blocking study revealed that 253J cells were recognised through NKG2D, while TCCSUP cells were mainly recognised through γδ T-cell receptor. VPA pre-treatment increased sensitivity to cytolysis by γδ T-cells for both cancer cell types, whereas ZOL pre-treatment was only effective against TCCSUP.


CONCLUSIONS
Induction of NKG2D ligands by VPA increased the susceptibility of cancer cells that are recognised by NKG2D to cytolysis by γδ T-cells.
Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan .
Toru
T
Suzuki
Shuji
S
Terao
Bishnu
B
Acharya
Michio
M
Naoe
Shingo
S
Yamamoto
Haruki
H
Okamura
Akinobu
A
Gotoh
D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D018682:GABA Agents / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014635:Valproic Acid / Q000494:pharmacology*
D018682:GABA Agents; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D012333:RNA, Messenger; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014635:Valproic Acid