|题名: ||Pharmacologically Upregulated Carcinoembryonic Antigen-expression Enhances the Cytolytic Activity of Genetically-modified Chimeric Antigen Receptor NK-92MI Against Colorectal Cancer Cells|
|作者: ||Masayuki Shiozawa, Chuan-Hsin Chang, Yi-Chun Huang, Yi-Ching Chen, Mau-Shin Chi, Hsu-Chao Hao, Yue-Cune Chang, Satoru Takeda, Kwan-Hwa Chi, Yu-Shan Wang|
|关键词: ||Natural killer cell;NK-92MI;Chimeric antigen receptor (CAR);Carcinoembryonic antigen (CEA);Cellular immunotherapy|
|上传时间: ||2018-08-15 12:10:25 (UTC+8)|
|摘要: ||Background: The natural killer cell line, NK-92MI, is cytotoxic against various types of cancer. The aim of this study
was to develop chimeric antigen receptor-modified (CAR) NK-92MI cells targeting carcinoembryonic antigenexpressing
(CEA) tumours and increase killing efficacy by pharmacologically modifying CEA-expression.
Result: We generated anti-CEA-CAR NK-92MI cells by retroviral vector transduction. This genetically-modified
cell line recognised and lysed high CEA-expressing tumour cell lines (LS174T) at 47.54 ± 12.60% and moderate
CEA-expressing tumour cell lines (WiDr) at 31.14 ± 16.92% at a 5:1 effector: target (E/T) ratio. The cell line did
not lyse low CEA-expressing tumour cells (HCT116) as they did their parental cells (NK-92MI cells). The histone
deacetylase-inhibitor (HDAC) sodium butyrate (NaB) and the methylation-inhibitor 5-azacytidine (5-AZA), as epigenetic
modifiers, induced CEA-expression in HCT116 and WiDr cells. Although the IC50 of 5 fluorouracil (5-FU) increased, both
cell lines showed collateral sensitivity to anti-CEA-CAR NK-92MI cells. The cytolytic function of anti-CEA-CAR NK-92MI
cells was increased from 22.99 ± 2.04% of lysis background to 69.20 ± 11.92% after NaB treatment, and 69.70 ± 9.93%
after 5-AZA treatment, at a 10:1 E/T ratio in HCT116 cells. The WiDr cells showed similar trend, from 22.99 ± 4.01% of
lysis background to 70.69 ± 10.19% after NaB treatment, and 59.44 ± 10.92% after 5-AZA treatment, at a 10:1 E/T ratio.
Conclusions: This data indicates that the effector-ability of anti-CEA-CAR NK-92MI increased in a CEA-dependent
manner. The combination of epigenetic-modifiers like HDAC-inhibitors, methylation-inhibitors, and adoptive-transfer of
ex vivo-expanded allogeneic-NK cells may be clinically applicable to patients with in 5-FU resistant condition.
|關聯: ||BMC Immunology 19(1):27(13 pages)|
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