乙型肝炎病毒致癌基因SALL4重新激活抵消PD-L1诱导的T细胞衰竭

StephenW

Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion

    Cheng Sun, Peixiang Lan, Qiuju Han, Mei Huang, Zhihong Zhang, Geliang Xu, Jiaxi Song, Jinyu Wang, Haiming Wei, Jian Zhang, Rui Sun, Cai Zhang & Zhigang Tian

    Nature Communicationsvolume 9, Article number: 1241 (2018)
    doi:10.1038/s41467-018-03584-3
    Download Citation
        CD8-positive T cellsHepatitis BImmune evasionTumour immunology

Received:
    24 January 2017
Accepted:
    26 February 2018
Published online:
    28 March 2018

Abstract

A chronic viral or tumor microenvironment can push T cells to exhaustion by promoting coinhibitory ligand expression. However, how host factors control coinhibitory ligand expression and whether viral infection breaks this control during tumor progress is unknown. Here we show a close negative correlation between SALL4 or PD-L1 and miR-200c in tumors from 98 patients with HBV-related hepatocellular carcinoma. SALL4 or PD-L1 expression correlates negatively with miR-200c expression, and patients with lower levels of SALL4 or PD-L1 and higher miR-200c survive longer. Moreover, over-expression of miR-200c antagonizes HBV-mediated PD-L1 expression by targeting 3ʹ-UTR of CD274 (encoding PD-L1) directly, and reverses antiviral CD8+ T cell exhaustion. MiR-200c transcription is inhibited by oncofetal protein SALL4, which is re-expressed through HBV-induced STAT3 activation in adulthood. We propose that an HBV-pSTAT3-SALL4-miR-200c axis regulates PD-L1. Therapeutic strategies to influence this axis might reverse virus-induced immune exhaustion.

StephenW

乙型肝炎病毒致癌基因SALL4重新激活抵消PD-L1诱导的T细胞衰竭中的miR-200c

    程孙兰培香韩秋菊黄梅张志宏许革良宋佳喜王金玉王海明魏健张健孙瑞蔡章田志刚

    Nature Communications第9卷，文章编号：1241（2018）
    DOI：10.1038 / s41467-018-03584-3
    下载引文
        CD8阳性T细胞肝炎免疫逃避肿瘤免疫学

收稿日期：
    2017年1月24日
公认：
    2018年2月26日
在线发布：
    2018年3月28日

抽象

慢性病毒或肿瘤微环境可以通过促进共抑制配体表达来推动T细胞衰竭。然而，宿主因子如何控制共抑制配体表达以及病毒感染在肿瘤进展期间是否打破这种控制是未知的。在这里，我们显示SALL4或PD-L1与miR-200c在来自98位HBV相关肝细胞癌患者的肿瘤中密切负相关。 SALL4或PD-L1表达与miR-200c表达呈负相关，SALL4或PD-L1水平较低且miR-200c水平较高的患者存活时间较长。此外，miR-200c的过表达通过直接靶向CD274的3'-UTR（编码PD-L1）来拮抗HBV介导的PD-L1表达，并逆转抗病毒CD8 + T细胞耗竭。 MiR-200c转录受到胎儿蛋白SALL4的抑制，其在成年期通过HBV诱导的STAT3激活而被再表达。我们建议HBV-pSTAT3-SALL4-miR-200c轴调节PD-L1。影响该轴的治疗策略可能会扭转病毒引起的免疫衰竭。

StephenW

https://www.nature.com/articles/ ... Id=MTM2NDQyMTk1NgS2