Kbtbd2 inhibits the cytotoxic activity of immortalized NK cells through downregulating mTOR signaling in a mouse hepatocellular carcinoma model

Kbtbd2 inhibits the cytotoxic activity of immortalized NK cells through downregulating mTOR signaling in a mouse hepatocellular carcinoma model

Abstract

Natural killer cell (NK cell)-based immunotherapy is a promising therapeutic strategy for hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the regulation of NK cell function in the tumor sites are not completely elucidated. In this study, we identified the enhanced expression of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) in intratumoral NK cells in a mouse HCC implantation model as a negative regulator of NK cells. To investigate this interaction, we used a Tet-on inducible expression system to control Kbtbd2 expression in an immortalized mouse NK cell line KIL C.2. With this approach, we found that overexpression of Kbtbd2reduced KIL C.2 cell proliferation, decreased expression certain of Ly49 receptor family members, and substantially impaired cytotoxic activityof KIL C.2 cells in vitro. Moreover, phosphorylation of mTOR and its target 4E-binding protein 1 was reduced in Kbtbd2-expressing KIL C.2 cells, along with down-regulated phosphorylation of Erk1/2. Adoptively transferred Kbtbd2-expressing KIL C.2 cells exhibited weaker tumoricidal effect on hepatocellular carcinoma cells in the HCC implantation model, in comparison with transferred control KIL C.2 cells. Taken together, our investigation indicates that Kbtbd2 is an inhibitory molecule for the tumoricidal activity of KIL C.2 cells and perhaps intratumoral NK cells.

Authors: Dai K1, Huang Y2, Chen Z3, Sun X1, Yang L1, Jiang Y1.

Influence Factor: 4.227

Citation: Eur J Immunol 48, 683-695 (2018).

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