Effect of irradiation-induced intercellular adhesion molecule-1 expression on natural killer cell-mediated cytotoxicity toward human cancer cells

• Published in: Cytotherapy (Oxford, England) England), 2018-05, Vol.20 (5), p.715-727
• Main Authors: Jeong, Jae-Uk, Uong, Tung Nguyen Thanh, Chung, Woong-Ki, Nam, Taek-Keun, Ahn, Sung-Ja, Song, Ju-Young, Kim, Sang-Ki, Shin, Dong-Jun, Cho, Eugene, Kim, Kyoung Won, Cho, Duck, Yoon, Mee Sun
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; immunotherapy; intercellular adhesion molecule-1; irradiation; natural killer cell; Other
• ISSN: 1465-3249; 1477-2566
• DOI: 10.1016/j.jcyt.2018.01.010

Abstract Background aims Irradiation enhances the adhesion between natural killer (NK) cells and target cells by up-regulating intercellular adhesion molecule-1 (ICAM-1) on target cells. Therefore, we investigated the effect of irradiation-induced ICAM-1 expression on human cancer cells on NK cell–mediated cytotoxicity. Methods Expression levels of ICAM-1 on the target cell surface before and after irradiation of six human cancer cell lines (HL60, SKBR-3, T47D, HCT-116, U937 and U251) were analyzed by flow cytometry. Ex vivo expansion of NK cells from human peripheral blood mononuclear cells was performed by co-culture with irradiated K562 cells. The related adhesion molecule lymphocyte function–associated antigen 1 (LFA-1) on NK cells was analyzed by flow cytometry. An enzyme-linked immunosorbent assay was used to detect interferon-γ (IFN-γ), and WST-8 assays were performed to check NK cell cytotoxicity. Finally, blocking assays were performed using monoclonal antibodies against ICAM-1 or LFA-1. Results LFA-1 expression increased on NK cells after expansion ( P  <   0.001). The expression of ICAM-1 was significantly upregulated by irradiation after 24 h in various cell lines, including HL60 ( P  <   0.001), SKBR-3 ( P  <   0.001), T47D ( P  <   0.001) and U937 ( P  <   0.001), although the level of expression depended on the cell line. ICAM-1 expression was extremely low before and after irradiation in U251 cells. NK cell–mediated cytotoxicity increased after irradiation of HL60 ( P  <   0.001), SKBR-3 ( P  <   0.001), T47D ( P  = 0.003), and U937 ( P  = 0.004) cells, in which ICAM-1 expression was significantly increased after irradiation. IFN-γ production by NK cells in response to HL60 ( P  <   0.001) and T47D ( P  = 0.011) cells significantly increased after irradiation. NK cell–mediated cytotoxicity against irradiated SKBR-3 ( P  <   0.001) and irradiated T47D cells ( P  = 0.035) significantly decreased after blocking of ICAM-1. Blocking of LFA-1 on NK cells resulted in reduced cytotoxicity against irradiated HL60 ( P  <   0.001) and irradiated SKBR-3 ( P  <   0.001). Conclusions Irradiation upregulates ICAM-1 expression on the surface of human cancer cells and enhances activated NK cell–mediated cytotoxicity. Therefore, irradiation combined with NK cell therapy may improve the antitumor effects of NK cells.