日本大阪大学Shizuo Akira团队近期取得重要工作进展，他们研究提出，mRNA内切酶Regnase-1的缺失通过oct2依赖的Ifng转录促进NK细胞抗肿瘤活性。相关研究成果2024年5月30日在线发表于《免疫》杂志上。

据介绍，肿瘤微环境（TME）中自然杀伤（NK）和T细胞的浸润和活性有限与免疫治疗反应不佳相关。

研究人员检测了核酸内切酶Regnase-1在NK细胞抗肿瘤活性中的作用。NK细胞特异性缺失Regnase-1（Reg1^ΔNK）增强了体外的细胞溶解活性和干扰素γ（IFN-γ）的产生，并增加了体内Reg1^ΔNK-NK细胞的瘤内积聚，减少了依赖于IFN-γ的肿瘤生长。Reg1^ΔNK-NK细胞的转录变化包括IFN-γ表达升高、细胞裂解效应物和趋化因子受体CXCR6。

IFN-γ诱导骨髓细胞上CXCR6配体CXCL16的表达，促进Reg1^ΔNK-NK细胞的进一步募集。从机制上讲，在白细胞介素（IL）-12和IL-18刺激后，Regnase-1缺失增加了其靶点，即转录调节因子OCT2和IκBζ，以及由此产生的OCT2-IκBζ-NF-κB复合物诱导的Ifng转录。人NK细胞中沉默Regnase-1增加了IFNG和POU2F2的表达。

总之，这一研究结果强调了TME中的NK细胞功能障碍，并提出靶向Regnase-1可以增强癌症免疫疗法中活性NK细胞的持久性。

附：英文原文

Title: Deletion of the mRNA endonuclease Regnase-1 promotes NK cell anti-tumor activity via OCT2-dependent transcription of Ifng

Author: Xin Sun, Yasuharu Nagahama, Shailendra Kumar Singh, Yuuki Kozakai, Hiroshi Nabeshima, Kiyoharu Fukushima, Hiroki Tanaka, Daisuke Motooka, Eriko Fukui, Eric Vivier, Diego Diez, Shizuo Akira

Issue&Volume: 2024-05-30

Abstract: Limited infiltration and activity of natural killer (NK) and T cells within the tumor microenvironment (TME) correlate with poor immunotherapy responses. Here, we examined the role of the endonuclease Regnase-1 on NK cell anti-tumor activity. NK cell-specific deletion of Regnase-1 (Reg1ΔNK) augmented cytolytic activity and interferon-gamma (IFN-γ) production in vitro and increased intra-tumoral accumulation of Reg1ΔNK-NK cells in vivo, reducing tumor growth dependent on IFN-γ. Transcriptional changes in Reg1ΔNK-NK cells included elevated IFN-γ expression, cytolytic effectors, and the chemokine receptor CXCR6. IFN-γ induced expression of the CXCR6 ligand CXCL16 on myeloid cells, promoting further recruitment of Reg1ΔNK-NK cells. Mechanistically, Regnase-1 deletion increased its targets, the transcriptional regulators OCT2 and IκBζ, following interleukin (IL)-12 and IL-18 stimulation, and the resulting OCT2-IκBζ-NF-κB complex induced Ifng transcription. Silencing Regnase-1 in human NK cells increased the expression of IFNG and POU2F2. Our findings highlight NK cell dysfunction in the TME and propose that targeting Regnase-1 could augment active NK cell persistence for cancer immunotherapy.

DOI: 10.1016/j.immuni.2024.05.006

Source: https://www.cell.com/immunity/fulltext/S1074-7613(24)00259-0