IFN-γ-induced PD-L1 expression represents the existence of tumor-specific T cells, which predicts high-response rate to anti-PD-1/L1 therapy, but loss-of-function of IFN signals (e.g., JAK mutation) induces adaptive immune resistance in patients with low-response rate. Interferon regulatory factors (IRF) are frequently epigenetic silenced in carcinogenesis, while the role of methylation in anti-PD-1/L1 therapy remains unclear. We here investigated the methylation status of IFN-γ related genes IRF1/8 and IFN-α/β-related genes IRF3/7 in lung cancer tissues and found that only highly methylated IRF1 and 7 negatively correlated to cd274 (coding PD-L1) expression, similar to JAK mutation. Interestingly, decitibine (DAC) as methylation inhibitor could hypomethylate IRF1/7 to restore PD-L1 level. Meanwhile, IRF7 enhanced constitutive PD-L1 expression, which was independent of IFN-γ though directly promote transcription of PD-L1, leading to abrogating cytotoxic T lymphocytes (CTLs) generation which could be restored by anti-PD-L1 antibody, or siRNA-IRF7. The supplement of DAC to anti-PD-1 therapy in vivo improve the efficiency of anti-tumor with less methylated IRF1/7, more interferon-related genes expression (e.g., CXCL9) and IFN-γ/CD8+ T-cells infiltrations, suggesting that additional treatment of DAC could rescue the ability to response to IFN in lung cancer patients with anti-PD-1/L1 therapy resistance.

中文翻译：

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Decitibine通过激活对肺癌细胞的IFN / PD-L1信号的响应来提高抗PD-1治疗的效率。

IFN-γ诱导的PD-L1表达代表肿瘤特异性T细胞的存在，这预示着对PD-1 / L1治疗的高应答率，但是IFN信号的功能丧失（例如JAK突变）在低应答率的患者中诱导适应性免疫抵抗。干扰素调节因子（IRF）在致癌作用中经常被表观遗传沉默，而甲基化在抗PD-1 / L1治疗中的作用仍不清楚。我们在这里调查了肺癌组织中与IFN-γ相关的基因IRF1 / 8和与IFN-α/β相关的基因IRF3 / 7的甲基化状态，发现只有高度甲基化的IRF1和7与cd274（编码PD-L1）负相关。表达，类似于JAK突变。有趣的是，地西他滨（DAC）作为甲基化抑制剂可以使IRF1 / 7发生次甲基化，从而恢复PD-L1的水平。同时，IRF7增强了本构性PD-L1表达，尽管它直接促进PD-L1的转录，但与IFN-γ无关，导致细胞毒性T淋巴细胞（CTL）的产生被废除，可以通过抗PD-L1抗体或siRNA-IRF7恢复。体内抗PD-1治疗的DAC补充通过减少甲基化的IRF1 / 7，更多的干扰素相关基因表达（例如CXCL9）和IFN-γ/ CD8 + T细胞浸润，提高了抗肿瘤的效率，表明DAC的额外治疗可以挽救具有抗PD-1 / L1治疗耐药性的肺癌患者对IFN的反应能力。