RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
ISG12a 通过阻断 TRIM21/AKT/β-catenin/PD-L1 轴促进 HBV 相关肝细胞癌的免疫治疗
英文原题：ISG12a promotes immunotherapy of HBV-associated hepatocellular carcinoma through blocking TRIM21/AKT/β-catenin/PD-L1 axis.
查看英文原题
ISG12a promotes immunotherapy of HBV-associated hepatocellular carcinoma through blocking TRIM21/AKT/β-catenin/PD-L1 axis.
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中文摘要
乙型肝炎病毒（HBV）感染通常在肝细胞中诱导较弱的I型干扰素（IFN）免疫应答，涵盖IFN刺激基因的调控作用。本研究中，低水平的IFN刺激基因12a（ISG12a）预示HBV相关肝细胞癌（HCC）的恶性转化和不良预后，而高水平的ISG12a则表明NK细胞表型活跃。ISG12a与TRIM21相互作用，抑制蛋白激酶B（PKB，又称AKT）和β-catenin的磷酸化激活，抑制PD-L1表达以阻断PD-1/PD-L1信号传导，从而增强NK细胞的抗癌效果。PD-1缺陷型NK-92细胞对HBV相关肿瘤的抑制作用不依赖于ISG12a表达，而PD-1表达型NK-92细胞对HBV相关肿瘤的抗癌效果则通过ISG12a以及atezolizumab和nivolumab的治疗得到增强。
因此，肿瘤内在的ISG12a通过调控PD-1/PD-L1信号传导促进NK细胞的抗癌效果，展现了先天免疫在抵御HBV相关HCC中的重要作用。
展开英文摘要原文
Hepatitis B virus (HBV) infection generally elicits weak type-I interferon (IFN) immune response in hepatocytes, covering the regulatory effect of IFN-stimulated genes. In this study, low level of IFN-stimulated gene 12a (ISG12a) predicted malignant transformation and poor prognosis of HBV-associated hepatocellular carcinoma (HCC), whereas high level of ISG12a indicated active NK cell phenotypes.
ISG12a interacts with TRIM21 to inhibit the phosphorylation activation of protein kinase B (PKB, also known as AKT) and β-catenin, suppressing PD-L1 expression to block PD-1/PD-L1 signaling, thereby enhancing the anticancer effect of NK cells. The suppression of PD-1-deficient NK-92 cells on HBV-associated tumors was independent of ISG12a expression, whereas the anticancer effect of PD-1-expressed NK-92 cells on HBV-associated tumors was enhanced by ISG12a and treatments of atezolizumab and nivolumab.
Thus, tumor intrinsic ISG12a promotes the anticancer effect of NK cells by regulating PD-1/PD-L1 signaling, presenting the significant role of innate immunity in defending against HBV-associated HCC.
论文信息
- 作者
- Deng R、Tian R、Li X、Xu Y、Li Y、Wang X、Li H、Wang L
- 单位
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, Hunan, China.China
- 期刊
- iScience2024 Apr 19
- 原文标识
- PubMed 38591006 · DOI 10.1016/j.isci.2024.109533
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