RRC ID 58077
著者 Saparbay J, Tanaka Y, Tanimine N, Ohira M, Ohdan H.
タイトル Everolimus enhances TRAIL-mediated anti-tumor activity of liver resident natural killer cells in mice.
ジャーナル Transpl Int
Abstract In transplantation, innate immunity plays a pivotal role in immunosurveillance and host defence against microbes and neoplastic cells. Liver-resident NK cells express TNF-related apoptosis-inducing ligand (TRAIL), which distinguishes them from conventional NK cells. In this study, we investigated the impact of mTOR inhibition on liver-resident NK cells in comparison with that on splenic NK cells in a mouse model. In mice that received everolimus (EVR) for 7 days (range: 0.0125-0.25 mg/kg/day), the proportion of splenic NK cells was unchanged, whereas the number of liver NK cells including TRAIL+ NK subpopulation increased for all doses of EVR. Consistently, liver-resident NK cells from the EVR-treated mice displayed enhanced cytotoxicity against TRAIL-sensitive neoplastic cells. EVR treatment inhibited the transition of the immature subset of liver NK cells to a mature state. The negative regulator of NK cells FoxO1 was activated as a consequence of impaired mTORC2-dependent AKT phosphorylation. Activated FoxO1 both reduced T-bet expression and induced TRAIL expression, thereby inhibiting NK cell maturation and promoting the antitumour activity of the immature subset of liver NK cells in response to EVR treatment. These findings indicate that EVR treatment enhances the antitumour activity of immature liver-resident NK cells through TRAIL upregulation.
巻・号 33(2)
ページ 229-243
公開日 2020-2-1
DOI 10.1111/tri.13536
PMID 31560810
MeSH Animals Cytotoxicity, Immunologic* Everolimus* / pharmacology Forkhead Box Protein O1 Killer Cells, Natural / drug effects* Liver / cytology* Mechanistic Target of Rapamycin Complex 2 Mice Neoplasms / immunology* Proto-Oncogene Proteins c-akt Spleen / cytology T-Box Domain Proteins TNF-Related Apoptosis-Inducing Ligand*
IF 3.526
引用数 0
リソース情報
ヒト・動物細胞 Hepa 1-6(RCB1638) YAC-1