Everolimus enhances TRAIL‐mediated anti‐tumor activity of liver resident natural killer cells in mice

Abstract

Summary 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.

Liver Regeneration in Chronic Liver Injuries: Basic and Clinical Applications Focusing on Macrophages and Natural Killer Cells

“…Considering the possible negative effects of LPLC-induced liver regeneration during chronic liver disease, such as liver fibrosis and hepatocarcinoma, NK cells have also been researched in such diseases. Recently, Saparbay et al 83 have demonstrated that the treatment of Everolimus could enhance the antitumor activity of immature liver-resident NK cells through the up-regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), consistent with an earlier study showing that liver-resident NK cells were distinctly characterized by expression of TRAIL, 84 which could attack virus-infected and tumor cells. 85 For liver fibrosis, NK cells could kill activated HSCs via RAE1/NKG2D- and TRAIL-dependent mechanisms, thereby controlling and ameliorating liver fibrosis, 86 indicating the important role of NK cells in suppressing liver fibrosis during hepatitis B virus or hepatitis C virus.…”

Crosstalk between NK cells and hepatic stellate cells in liver fibrosis (Review)

“…Currently, increasing studies have identified various receptor-ligand signals between NK cells and their target cells ( 21 ), and several crucial signals will be discussed below. The activated NK cells kill the target cells through several mechanisms: granule exocytosis, death receptor-mediated apoptosis ( 22 , 23 ), and cytokine secretion ( 24 ). Thus, activation of NK cells is expected to becoming a promising strategy to halt the progression of liver diseases.…”

Cytotoxic immune cell-based immunotherapy for hepatocellular carcinoma

“…Fortunately, IL-15 could recover HCC-induced liver-resident NK-cell dysfunction [37] . In addition, the mTOR inhibitor -everolimus -enhances their anticancer activity through upregulation of TRAIL [39] . Thus, liver-resident NK cells have the potential for application in HCC therapy, although the complete underlying mechanism of liver-resident NK cells' exhaustion remains unclear.…”