LINC02470 impairs natural killer cell cytotoxicity by epigenetically targeting the natural cytotoxicity triggering receptor 1

Introduction Natural killer cells (NK cells) play a critical role in the surveillance of tumor immunity. However, NK cell-based immunotherapy, including autologous and allogeneic NK cell reinfusion, has not brought significant clinical benefits to patients. Methods To identify factors that control the intrinsic cytotoxicity of NK cells, we utilized the histone deacetylase inhibitor valproic acid (VPA) to develop a NK cell cytotoxicity suppression model. With RNA-seq and functional assays, we identified a lncRNA, LINC02470 , as a negative regulatory factor of NK cell-mediated cytotoxicity. LINC02470 was significantly upregulated in VPA-treated NK cells and was negatively associated with the cytotoxicity of NK cells. Knockdown of LINC02470 enhanced, and overexpression of LINC02470 suppressed antitumor activity in NK-92MI cells and human primary NK cells. Then reverse transcription-associated capture sequencing (RAT-seq) and mechanistic studies were explored to find the target and mechanisms of LINC02470 . Results By RAT-seq we found that LINC02470 functioned by targeting the Natural cytotoxicity triggering receptor 1 ( NCR1 ) gene, which encodes the activating receptor NKp46 involved in the natural cytotoxicity. Mechanistic studies revealed that LINC02470 interacted with the regulatory elements of NCR1 and blocked the formation of an intrachromosomal interaction that is required for optimal expression of NCR1 . In addition, LINC02470 inhibited the synthesis of NCR1 enhancer RNA. Through these dual mechanisms, LINC02470 induced a suppressive epigenotype in the NCR1 promoter and suppressed the expression of the NCR1 gene. Discussion The LINC02470-NCR1 axis identified in this study may serve as a novel target to improve therapeutic intervention of NK cells in tumor immunotherapy.