State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingJiangsuChina.
Institute of Biomedical Research (BIOMED)Catholic University of ArgentinaBuenos AiresArgentina.
Hepatology. 2022 Dec;76(6):1602-1616. doi: 10.1002/hep.32316. Epub 2022 Jan 24.
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 patients with HCC for unknown reasons. Evidence reveals 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 (IRF) 8 in HCC, among all the nine IRF members that regulate interferon signals, was associated with poor prognosis of patients with HCC. Moreover, gene set enrichment analysis identified the interferon-gamma and PD-1 signaling signatures as the top suppressed pathways in patients with IRF8-low HCC. Contrarily, overexpression of IRF8 in HCC cells significantly enhanced antitumor effects in immune-competent mice, modulating infiltration of tumor-associated macrophages (TAMs) and T cell exhaustion in tumor microenvironment. We further demonstrated that IRF8 regulated recruitment of TAMs by inhibiting the expression of chemokine (C-C motif) ligand 20 (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.
This work identified IRF8 as an important prognostic biomarker in patients with HCC that predicted the response and sensitivity to anti-PD-1 therapy and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.
程序性细胞死亡蛋白-1（PD-1）免疫检查点途径的治疗性阻断导致 T 细胞介导的抗肿瘤免疫的显著再激活，并且是几种肿瘤类型中很有前途的临床抗癌治疗方式，但由于未知原因，大多数 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发挥着关键作用，但机制尚不清楚。
我们使用基于 HCC 数据库的 Kaplan-Meier 生存分析发现，干扰素调节因子（IRF）8 在 HCC 中的表达缺失，在调节干扰素信号的所有 9 个 IRF 成员中，与 HCC 患者的预后不良相关。此外，基因集富集分析确定干扰素-γ和 PD-1 信号通路是 IRF8 低 HCC 患者中被抑制的前 2 大通路。相反，IRF8 在 HCC 细胞中的过表达显著增强了免疫功能正常小鼠的抗肿瘤作用，调节肿瘤相关巨噬细胞（TAM）和 T 细胞衰竭在肿瘤微环境中的浸润。我们进一步证明，IRF8 通过抑制趋化因子（C-C 基序）配体 20（CCL20）的表达来调节 TAM 的募集。在机制上，IRF8 介导的 c-fos 转录抑制导致 CCL20 的表达降低，而不是直接结合 CCL20 启动子区域。重要的是，腺相关病毒 8 介导的肝 IRF8 挽救显著抑制 HCC 进展并增强对抗 PD-1 治疗的反应。
这项工作确定了 IRF8 作为 HCC 患者的一个重要预后生物标志物，预测了对抗 PD-1 治疗的反应和敏感性，并揭示了它作为增强免疫治疗疗效的治疗靶点。
