RRC ID 44960
Author Mimura K, Kamiya T, Shiraishi K, Kua LF, Shabbir A, So J, Yong WP, Suzuki Y, Yoshimoto Y, Nakano T, Fujii H, Campana D, Kono K.
Title Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer.
Journal Int J 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.
Volume 135(6)
Pages 1390-8
Published 2014-9-15
DOI 10.1002/ijc.28780
PMID 24615495
MeSH Animals Antibody-Dependent Cell Cytotoxicity Cell Line, Tumor Humans Immunotherapy, Adoptive / methods* Interleukin-2 / immunology Interleukin-2 / pharmacology K562 Cells Killer Cells, Natural / drug effects Killer Cells, Natural / immunology* Mice Mice, Inbred NOD Mice, SCID NK Cell Lectin-Like Receptor Subfamily K / biosynthesis Receptor, ErbB-2 / biosynthesis Stomach Neoplasms / blood Stomach Neoplasms / immunology Stomach Neoplasms / therapy*
IF 5.145
Times Cited 24
Human and Animal Cells MKN45(RCB1001)