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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.

Author information

Jeong JU1, Uong TNT2, Chung WK1, Nam TK1, Ahn SJ1, Song JY1, Kim SK3, Shin DJ4, Cho E5, Kim KW2, Cho D6, Yoon MS7.
1
Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea.
2
Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Jeollanam-do, Republic of Korea; Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, Republic of Korea.
3
Department of Companion & Laboratory Animal Science, Kongju National University, Yesan, Republic of Korea.
4
Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Jeollanam-do, Republic of Korea; Department of Companion & Laboratory Animal Science, Kongju National University, Yesan, Republic of Korea.
5
Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea; Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Jeollanam-do, Republic of Korea.
6
Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
7
Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea; Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Jeollanam-do, Republic of Korea; Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, Republic of Korea. Electronic address: meesunyoon@jnu.ac.kr.