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Int J Biol Sci 2018; 14(3):331-340. doi:10.7150/ijbs.22809

Research Paper

Effect of IL-18 on the Expansion and Phenotype of Human Natural Killer Cells: Application to Cancer Immunotherapy

Hiroaki Senju1,2,3, Asuka Kumagai2, Yoichi Nakamura1,3, Hiroyuki Yamaguchi1,3, Katsumi Nakatomi1,3, Shota Fukami2, Kengo Shiraishi2, Yuka Harada2, Mitsuhiro Nakamura2, Haruki Okamura4, Yoshimasa Tanaka2,4✉, Hiroshi Mukae1,3

1. Department of Respiratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
2. Center for Bioinformatics and Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
3. Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
4. Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan

Abstract

When pathogenic stresses are recognized by innate immune cells, inflammasomes are assembled and caspase-1 is activated, resulting in the conversion of pro-IL-18 into mature IL-18. Because natural killer (NK) cells express IL-18 receptors, IL-18 may play roles in immune functions of NK cells. In the present study, we examined the effect of IL-18 on NK cells derived from lung cancer patients and healthy adult volunteers. When peripheral blood NK cells were stimulated with IL-2, the cells formed clusters beginning on day 5-6 and proliferated thereafter, in which the number of NK cells increased by 10-fold in 10 days. When IL-18 was added, cell clusters were observed as early as on day 4 and NK cells proliferated vigorously. On day 10, the expansion rate was 56-fold on average, showing that IL-18 promoted the expansion of NK cells. It was also notable that IL-18 enhanced the expression of CD80, CD86, HLA-DR and HLA-DQ on NK cells, suggesting that IL-18 conferred NK cells an APC-like phenotype. When cellular cytotoxicity was determined, APC-like NK cells efficiently killed tumor cells and anti-tumor activity was augmented by the addition of tumor antigen-specific mAbs. In addition, IFN-γ was produced by APC-like NK cells in response to tumor cells, and the cytokine production was further enhanced by mAbs. Taken together, IL-18 not only promoted the expansion of NK cells, but also changed the phenotype of NK cells. IL-2/IL-18-induced NK cells might, therefore, serve as a bridge between innate immunity and adaptive immunity and be useful for cancer immunotherapy.

Keywords: IL-18, NK cells, antigen-presenting cells, PD-1, immune checkpoint

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How to cite this article:
Senju H, Kumagai A, Nakamura Y, Yamaguchi H, Nakatomi K, Fukami S, Shiraishi K, Harada Y, Nakamura M, Okamura H, Tanaka Y, Mukae H. Effect of IL-18 on the Expansion and Phenotype of Human Natural Killer Cells: Application to Cancer Immunotherapy. Int J Biol Sci 2018; 14(3):331-340. doi:10.7150/ijbs.22809. Available from http://www.ijbs.com/v14p0331.htm