mTOR Inhibitors Enhance Antitumor Activity of Liver Resident NK Cells

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Abstract

Background

The immunosuppressive regimen currently used after organ transplantation reduces adaptive components. Therefore, the innate immune cells play pivotal roles in immune surveillance and defense against microbes and neoplastic cells after transplantation. Although the mTOR inhibitor (mTORi) is known as an immunosuppressive drug as well as a molecular targeting anti-cancer drug, its effects on innate immune cells is unclear. In this study, we analyzed the influence of mTORi on natural Killer (NK) cell subpopulations in mice.

Methods

C57/BL6 mice were treated by intraperitoneal injection of mTORi in three different dose(0-0.25mg/kg) for 7 days. Twenty four hours after the last injection, liver mononuclear cells (LMNCs), splenocytes and peripheral blood (PB) mononuclear cells were collected. The proportion of NK cells and various functional molecules on NK cells were analyzed by flow cytometry.

Methods

The cytotoxic activity of liver NK cells against hepatocellular carcinoma was analyzed by 51Cr release assay.

Results

The proportion of TCR-NK1.1+NK fraction in LMNCs did not differ in both mTORi-treated and -untreated groups (11.0±0.3% vs 11.3±1.6%, respectively). However, mTORi significantly upregulated the expression level of TRAIL on liver NK cells in dose dependency (26.2±2.0 in 0.0125 mg/kg dose group, 27.0±2.0 in 0.0250 mg/kg dose group, 25.6±1.0 in 0.25 mg/kg dose group vs 18.5±4.76 in untreated, p=0.05, p= 0.02, p =0.03 respectively). Expression of NKp46 and CD69 was also higher in mTORi-treated group (117.7±3.7 vs 96.2±3.5, 54.1±6.04 vs 46.8±12.15, respectively). mTORi treatment increased the EOMES+ NK cell subset (43.5%±13 in mTORi – in treated group vs19.9 %±6.2 in untreated group, p=0.03).The proportion of NK cells, expression of their activation markers in the spleen were not affected by mTORi treatment. Liver NK cells from mTORi treated mice showed significantly higher cytotoxicity against TRAIL-sensitive Hepa1-6 cells (30.1% ± 13.0 vs 13.5 %± 6.0, p=0.009). Cytotoxicity against TRAIL resistant YAC-1 mouse lymphoma was also enhanced after mTORi treatment (53.6 % ± 4.4 vs 39.9% ± 1.2).

Conclusion

mTOR inhibitor has ability to enhance liver resident NK cell activity. This result suggests that mTOR inhibitor might be useful to maintain anti-microbe and anti-tumor immunity even under immunosuppressive condition after transplantation.

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