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    Title: Pharmacologically Upregulated Carcinoembryonic Antigen-expression Enhances the Cytolytic Activity of Genetically-modified Chimeric Antigen Receptor NK-92MI Against Colorectal Cancer Cells
    Authors: Shiozawa, Masayuki;Chang, Chuan-Hsin;Huang, Yi-Chun;Chen, Yi-Ching;Chi, Mau-Shin;Hao, Hsu-Chao;Chang, Yue-Cune;Takeda, Satoru;Chi, Kwan-Hwa;Wang, Yu-Shan
    Keywords: Natural killer cell;NK-92MI;Chimeric antigen receptor (CAR);Carcinoembryonic antigen (CEA);Cellular immunotherapy
    Date: 2018-08-03
    Issue Date: 2019-03-16 12:10:41 (UTC+8)
    Abstract: 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 antigen-expressing (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.
    Relation: BMC Immunology 2018 3(19), p.1-13
    DOI: 10.1186/s12865-018-0262-z
    Appears in Collections:[Graduate Institute & Department of Mathematics] Journal Article

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