|標題：Pharmacologically Upregulated Carcinoembryonic Antigen-expression Enhances the Cytolytic Activity of Genetically-modified Chimeric Antigen Receptor NK-92MI Against Colorectal Cancer Cells|
|作品名稱||Pharmacologically Upregulated Carcinoembryonic Antigen-expression Enhances the Cytolytic Activity of Genetically-modified Chimeric Antigen Receptor NK-92MI Against Colorectal Cancer Cells|
|著者||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|
|著錄名稱、卷期、頁數||BMC Immunology 2018 3(19), p.1-13|
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 antigen-expressing (CEA) tumours and increase killing efficacy by pharmacologically modifying CEA-expression.
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.
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.
|關鍵字||Natural killer cell;NK-92MI;Chimeric antigen receptor (CAR);Carcinoembryonic antigen (CEA);Cellular immunotherapy|