Hepatic interferon regulatory factor 8 expression suppresses hepatocellular carcinoma progression and enhances the response to anti-programmed cell death protein-1 therapy.
Hepatic interferon regulatory factor 8 expression suppresses hepatocellular carcinoma progression and enhances the response to anti-programmed cell death protein-1 therapy.
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肝干扰素调节因子 8 表达可抑制肝细胞癌进展并增强抗程序性细胞死亡蛋白 1 疗法的反应
DOI：
10.1002/hep.32316
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发表时间：
2022-12
期刊：
影响因子：
13.5
通讯作者：
Yang, Yong
中科院分区：
文献类型：
--
作者：
Wu, Hongxi;Li, Yan;Shi, Guangjiang;Du, Shijia;Wang, Xiaobin;Ye, Wanli;Zhang, Zixuan;Chu, Ya;Ma, Shuqian;Wang, Dajia;Li, Yuan;Chen, Zhen;Birnbaumer, Lutz;Wang, Zhuo;Yang, Yong
程序性细胞死亡蛋白-1（PD-1）免疫检查点通路的治疗性阻断可显著激活T细胞介导的抗肿瘤免疫力，是几种肿瘤类型中有前景的临床抗癌治疗方式，但由于未知原因，大多数肝细胞癌（HCC）患者的持久缓解率仍然相对较低（15-20%）。有证据表明干扰素信号通路在调节抗PD-1治疗对多种肿瘤类型的疗效和敏感性方面起着关键作用，但其机制尚不清楚。使用Kaplan-Meier生存分析HCC数据库的基础上，我们发现，在所有9个干扰素调节因子（IRF）成员中，干扰素调节因子（IRF 8）在HCC中的表达下降与HCC患者的不良预后相关。此外，基因集富集分析将IFN-γ和PD-1信号传导特征鉴定为IRF 8低HCC患者中的最高抑制途径。间接地，IRF 8在HCC细胞中的过表达显著增强免疫活性小鼠中的抗肿瘤效应，调节肿瘤相关巨噬细胞（TAM）的浸润和肿瘤微环境中的T细胞耗竭。我们进一步证明了IRF 8通过抑制CCL 20的表达来调节TAM的募集。在机制上，IRF 8介导的c-fos转录的抑制导致CCL 20的表达降低，而不是直接结合到CCL 20启动子区域。重要的是，腺相关病毒8介导的肝脏IRF 8拯救显著抑制了HCC进展，并增强了对抗PD-1治疗的反应。最后：这项工作将IRF 8确定为HCC患者的重要预后生物标志物，可预测抗PD-1治疗的反应和敏感性，并将其作为增强免疫治疗疗效的新治疗靶点。
Therapeutic blockade of the programmed cell death protein-1 (PD-1) immune checkpoint pathways has resulted in significant reactivation of T-cell mediated antitumor immunity and is a promising clinical anticancer treatment modality in several tumor types, but the durable response rate remains relatively low (15–20%) in most hepatocellular carcinoma (HCC) patients for unknown reasons. Evidences reveal that the interferon signaling pathway plays a critical role in modulating the efficacy and sensitivity of anti-PD-1 therapy against multiple tumor types, but the mechanisms are unclear. Using Kaplan-Meier survival analysis based on HCC databases, we found that deceased expression of interferon regulatory factor (IRF8) in HCC, among all the nine IRF members which regulate interferon signals, was associated with the poor prognosis of HCC patients. Moreover, gene set enrichment analysis identified the IFN-gama and PD-1 signaling signatures as the top suppressed pathways in IRF8 low HCC patients. Contrarily, overexpression of IRF8 in HCC cells significantly enhanced antitumor effects in immune-competent mice, modulating infiltration of tumor associated macrophages (TAMs) and T cells exhaustion in tumor microenvironment. We further demonstrated that IRF8 regulated recruitment of TAMs by inhibiting the expression of CCL20. Mechanically, IRF8-mediated repression of c-fos transcription resulted in decreased expression of CCL20, rather than directly bound to CCL20 promoter region. Importantly, adeno-associated virus 8-mediated hepatic IRF8 rescue significantly suppressed HCC progression and enhanced the response to anti-PD-1 therapy. In conclusion: This work identified IRF8 as an important prognostic biomarker in HCC patients which predicted the response and sensitivity to anti-PD-1 therapy and uncovered it as a new therapeutic target for enhancing the efficacy of immune therapy.
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影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
影响因子：
25.7
作者：
Marquardt JU;Factor VM;Thorgeirsson SS
通讯作者：
Thorgeirsson SS
影响因子：
64.5
作者：
Sheng W;LaFleur MW;Nguyen TH;Chen S;Chakravarthy A;Conway JR;Li Y;Chen H;Yang H;Hsu PH;Van Allen EM;Freeman GJ;De Carvalho DD;He HH;Sharpe AH;Shi Y
通讯作者：
Shi Y
DOI：
10.4049/jimmunol.1501466
发表时间：
2016-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fang C;Qiao Y;Mun SH;Lee MJ;Murata K;Bae S;Zhao B;Park-Min KH;Ivashkiv LB
通讯作者：
Ivashkiv LB