Mesothelin-targeting chimeric antigen receptor-modified T cells by piggyBac transposon system suppress the growth of bile duct carcinoma.
Tumour Biol
; 39(4): 1010428317695949, 2017 Apr.
Article
em En
| MEDLINE
| ID: mdl-28381173
ABSTRACT
Chimeric antigen receptor modified T cell-based immunotherapy is revolutionizing the field of cancer treatment. However, its potential in treating bile duct carcinoma has not been fully explored. Herein, we developed the second-generation mesothelin-targeting chimeric antigen receptor-modified T cells with the 4-1BB co-stimulatory module by the piggyBac transposon system. Mesothelin-targeting chimeric antigen receptor was expressed by 66.0% of mesothelin-targeting chimeric antigen receptor-modified T cells post electrophoretic transfection and stimulation with K562-meso cells; the expressions of activation markers were tested by flow cytometry assay and showed greater activation of mesothelin-targeting chimeric antigen receptor-modified T cells than control T cells (CD107α 71.9% vs 48.6%; CD27 92.1% vs 61.8%; CD137 55.5% vs 8.4%; CD28 98.0% vs 82.1%; CD134 37.5% vs 10.4%). Furthermore, mesothelin-targeting chimeric antigen receptor-modified T cells exerted cytotoxicity toward mesothelin-expressing EH-CA1b and EH-CA1a cells in an effector-to-target ratio-dependent manner, while leaving mesothelin-negative GSC-SD and EH-GB1 cells and normal liver L02 cells almost unharmed. Mesothelin-targeting chimeric antigen receptor-modified T cells secreted cytokines at higher levels when co-cultured with mesothelin-positive EH-CA1a and EH-CA1b cells than with mesothelin-negative GSC-SD and EH-GB1 cells. Enhanced cytotoxicity and cytokine secretion of mesothelin-targeting chimeric antigen receptor-modified T cells compared to control T cells were also observed when co-cultured with 293-meso cells (interferon γ 85.1% ± 1.47% vs 8.3% ± 2.50%, p = 0.000; tumor necrosis factor α 90.9% ± 4.67% vs 18.5% ± 3.62%, p = 0.0004; interleukin 2 60.8% ± 2.00% vs 15.6% ± 2.06%, p = 0.002; interleukin 6 6.4% ± 2.95% vs 1.7% ± 0.63%, p = 0.055). In addition, mesothelin-targeting chimeric antigen receptor-modified T cells showed greater inhibitory and proliferative capability than control T cells within EH-CA1a cell xenografts. This study shows the potential of mesothelin-targeting chimeric antigen receptor-modified T cells in treating bile duct carcinoma.
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Assunto principal:
Neoplasias dos Ductos Biliares
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Elementos de DNA Transponíveis
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Receptores de Antígenos de Linfócitos T
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Linfócitos T
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Proteínas Ligadas por GPI
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Imunoterapia
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article