MicroRNA-422a downregulates DNAM-1 expression in NK cells and impairs DNAM-1-mediated cytotoxicity (TUM10P.1033)

Abstract

Abstract Natural killer (NK) cells play a crucial role in innate immunity against cancer. Activation of NK cells is regulated by a balance between activating and inhibitory signals from cell surface receptors. Among these receptors, DNAM-1 and its ligands ( PVR and Nectin-2) play a vital role in NK cell-mediated recognition and lysis of tumor cells. microRNAs (miRNAs) are key regulators of gene expression that may be involved in NK function of immune surveillance against cancer. Several miRNA have been identified as modulators of NK activating receptor and its ligands expression, such as NKG2D and MICA. However, little is known about DNAM-1 gene regulation by miRNA. Based on bioinformatics, we identified miR-422a with putative docking sites in the 3'UTR of DNAM-1. Furthermore, we investigated the potential interaction between the 3'UTR of DNAM-1 gene and miR-422a as well as its functional role in the regulation of DNAM-1 expression and cytotoxicity in NK cells both in vitro and in vivo. We found that TGF-β1 but not L-kynurenine upregulated miR-422a expression in NK cells, resulting in markedly inhibiting NK cytotoxicity against lung cancer cells, which was mediated by suppression of DNAM-1. Conversely, miR-422a downregulation significantly increased DNAM-1 expression in NK cells, resulting in more efficient DNAM-1-mediated cytotoxicity. Our findings indicate that miR‑422a is a novel regulator for DNAM-1. Therapeutic control of miR-422a may provide new strategies against lung cancer.