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Implication of Highly Cytotoxic Natural Killer Cells for Esophageal Squamous Cell Carcinoma Treatment

Lim, Kee, Siang*; Mimura, Kosaku†,‡,§; Kua, Ley-Fang; Shiraishi, Kensuke; Kono, Koji†,‡,#

doi: 10.1097/CJI.0000000000000227
Basic Studies

Esophageal squamous cell carcinoma (ESCC) is an aggressive upper gastrointestinal cancer and effective treatments are limited. Previous studies reported that natural killer (NK) cells expanded by coculturing with K562-mb15-41BBL feeder cells, a genetically modified K562 leukemia cell line that expresses membrane-bound interleukin (IL)-15 and 41BBL ligand, were highly proliferative and highly cytotoxic. Here, we investigated the potential of expanded NK cells for ESCC treatment. We analyzed both genetic and surface expression levels of NKG2D ligands (NKG2DLs) in ESCC using publicly available microarray data sets and ESCC cell lines. The cytotoxicity of resting and of IL-2-activated NK cells against ESCC cell lines was compared with that of expanded NK cells. We then also investigated the effect of epithelial mesenchymal transition (EMT) inducers, GSK3β inhibitor and epidermal growth factor, on NKG2DLs expressions. As a result, MICA and MICB were significantly overexpressed in ESCC compared with adjacent normal tissues and surface NKG2DLs were expressed in ESCC cell lines. Expanded NK cells were much potent than IL-2-activated and resting NK cells against ESCC cell lines. Blocking of NKG2D with anti-NKG2D monoclonal antibody dampened expanded NK cell cytotoxicity, suggesting that the NKG2DLs-NKG2D interaction is crucial for NK cells to eliminate ESCC cells. EMT inducers concurrently induced EMT and NKG2DLs expression in ESCC cell lines rendering transitioned cells more sensitive to expanded NK cells. In conclusion, expanded NK cells were highly cytotoxic against NKG2DLs-expressing ESCC cells, particularly the EMT phenotype. These results provide a strong rationale for clinical use of these NK cells in ESCC patients.

*Cancer Science Institute of Singapore

Department of Hematology-Oncology, National University of Singapore, Singapore

Departments of Gastrointestinal Tract Surgery

Advanced Cancer Immunotherapy

§Progressive DOHaD Research

#Organ Regulatory Surgery, Fukushima Medical University, Fukushima City, Fukushima

Department of Surgery, Fujikawa Hospital, Kyonan Medical Center, Kajikazawa Fujikawa-cho, Minamikoman-gun, Yamanashi, Japan

Reprints: Koji Kono, Department of Gastrointestinal Tract Surgery, Department of Advance Cancer Immunology, and Department of Organ Regulatory Surgery, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan (e-mail:

Received December 1, 2017

Accepted March 21, 2018

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