Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer (Int J Cancer, Sept 2014)

Kousaku Mimura1, Takahiro Kamiya2, Kensuke Shiraishi1,6, Ley-Fang Kua3, Asim Shabbir1, Jimmy So1, Wei-Peng Yong3, Yoshiyuki Suzuki4, Yuya Yoshimoto4, Takashi Nakano4, Hideki Fujii6, Dario Campana2 and Koji Kono1,5

1 Department of Surgery, National University of Singapore
2 Department of Pediatrics, National University of Singapore
3 Department of Hematology-Oncology, National University of Singapore
4 Department of Radiation Oncology, Gunma University Graduate School of Medicine, Japan
5 Cancer Science Institute of Singapore, National University of Singapore
6 First Department of Surgery, University of Yamanashi, Japan

Address correspondence to: Koji Kono, PhD, MD
Department of Surgery, National University of Singapore
Level 8, NUHS Tower Block, 1E Kent Ridge Road, 119228 Singapore
Office phone +65 6772 3196 Fax +65 6777 8427
Email; surkoji[at]

To develop more effective therapies for patients with advanced gastric cancer, we examined the potential of ex vivo expanded natural killer (NK) cells. We assessed the expression of ligands for NK Group 2 Member D (NKG2D, an important NK activation molecule) in primary tumors from 102 patients with gastric cancer by immunohistochemistry and determined their prognostic value. We then examined the in vitro and in vivo cytotoxicity of NK cells from healthy donors and patients with gastric cancer. The cytotoxicity of resting and of interleukin (IL)-2-activated NK cells was compared to that of NK cells expanded for 7 days by coculture with the K562-mb15-4.1BBL cell line. As a result, the expression of NKG2D ligands in primary tumors was correlated with favorable presenting features and outcomes, suggesting that gastric cancer may be sensitive to NK cell cytotoxicity. Although resting NK cells showed minimal cytotoxicity against gastric cancer cells, K562-mb15-4.1BBL-expanded NK cells were highly cytotoxic and significantly more powerful than IL-2-activated NK cells. Cytotoxicity was correlated with NKG2D ligand expression and could be modulated by mitogen-activated protein kinase and AKT-PI3 kinase inhibitors. The cytotoxicity of expanded NK cells against HER2-positive gastric cancer cells could be increased by Herceptin and further augmented by Lapatinib. Finally, expanded NK cells exhibited strong antitumor activity in immunodeficient mice engrafted with a gastric cancer cell line. In conclusion, gastric cancer tumors express NKG2D ligands and are highly susceptible to killing by NK cells stimulated by K562-mb15-4.1BBL. These results provide a strong rationale for clinical testing of these NK cells in patients and suggest their use to augment the effects of antibody therapy.