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NKCLR3 impairs natural killer cell cytotoxicity by epigenetically targeting the Natural Cytotoxicity Triggering Receptor 1 (NCR1) [lncRNA-seq]

ABSTRACT: 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. 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 previously uncharacterized lncRNA, NKCLR3 (NK cytotoxicity-associated long noncoding RNA 3), as a negative regulatory factor of NK cell-mediated cytotoxicity. NKCLR3 was significantly upregulated in VPA-treated NK cells and was negatively associated with the cytotoxicity of NK cells. Knockdown of NKCLR3 enhanced antitumor activity in NK-92MI cells. Using reverse transcription-associated capture sequencing (RAT-seq), we found that NKCLR3 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 NKCLR3 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, NKCLR3 inhibited the synthesis of NCR1 enhancer RNA. Through these dual mechanisms, NKCLR3 induced a suppressive epigenotype in the NCR1 promoter and suppressed the expression of the NCR1 gene. Thus, the NKCLR3-NCR1 axis identified in this study may serve as a novel target to improve therapeutic intervention of NK cells in tumor immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285271 | GEO | 2025/01/01

REPOSITORIES: GEO

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Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.

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NKCLR3 impairs natural killer cell cytotoxicity by epigenetically targeting the Natural Cytotoxicity Triggering Receptor 1 (NCR1) [lncRNA-seq]

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