title: Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer.
abstract: 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.
authors.affiliation: Department of Surgery, National University of Singapore, Singapore, Singapore.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Mimura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kamiya
authors.forename: Kensuke
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Ley-Fang
authors.initials: LF
authors.lastname: Kua
authors.forename: Asim
authors.initials: A
authors.lastname: Shabbir
authors.forename: Jimmy
authors.initials: J
authors.lastname: So
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Yong
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yoshimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: Koji
authors.initials: K
authors.lastname: Kono
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D045744:Cell Line, Tumor; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000097:blood / Q000276:immunology / Q000628:therapy*
chemical_list: D007376:Interleukin-2; D055655:NK Cell Lectin-Like Receptor Subfamily K; D018719:Erb-b2 Receptor Tyrosine Kinases; C527085:KLRK1 protein, human; C508053:ERBB2 protein, human
keywords: ADCC; MICs; NK cells; NKG2D; ULBPs; gastric cancer