INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.
Université Paris-Est Créteil, Créteil, France.
Liver Int. 2020 Jan;40(1):74-82. doi: 10.1111/liv.14226. Epub 2019 Sep 4.
BACKGROUND & AIMS: The recent approval of direct acting anti-virals (DAA) has dramatically changed the landscape of hepatitis C virus (HCV) therapy. Whether viral clearance could promote liver carcinogenesis is debated. It has been hypothesized that changes in intrahepatic immune surveillance following viral cure could favour tumour growth. This study aimed at characterizing the intrahepatic immune changes induced by HCV cure following DAA therapy.
Patients with compensated cirrhosis who underwent surgical resection for hepatocellular carcinoma (HCC) after sustained virological response (SVR) to DAA therapy were included. A control group of untreated HCV-infected patients with compensated cirrhosis was selected. RNA was extracted from tumoral and non-tumoral tissues and analysed using the Nanostring Immuno-Oncology-360 panel. Immune cells were quantified by immunohistochemistry.
Twenty patients were included: 10 patients with a DAA-induced SVR and 10 untreated controls. All of them had a de novo BCLC 0/A HCC. Non-tumoral tissue profiling showed down-regulation of interferon-related genes (including MX1, ISG15 and IFIT1) after DAA therapy. No other differences in immune profiles/immune cell densities were identified between the two groups. The intra-tumoral immune profiles of HCCs that occurred after DAA therapy were not qualitatively or quantitatively different from those of tumours occurring in untreated patients.
In conclusion, removal of HCV infection after DAA-based therapy results only in a down-regulation of interferon-stimulated genes in non-tumoral tissues from patients with cirrhosis who develop HCC. These minor changes in the liver immune microenvironment are unlikely to favour HCC occurrence or recurrence after DAA-induced SVR.
直接作用抗病毒药物（DAA）的最近获批极大地改变了丙型肝炎病毒（HCV）治疗的格局。病毒清除是否能促进肝癌发生仍存在争议。有人假设，病毒治愈后肝内免疫监视的变化可能有利于肿瘤生长。本研究旨在描述 DAA 治疗后 HCV 治愈引起的肝内免疫变化。
纳入因 DAA 治疗持续病毒学应答（SVR）后接受肝癌（HCC）手术切除的代偿性肝硬化患者。选择一组未经治疗的代偿性肝硬化 HCV 感染患者作为对照组。从肿瘤和非肿瘤组织中提取 RNA，并使用 Nanostring 免疫肿瘤学-360 面板进行分析。通过免疫组织化学定量免疫细胞。
共纳入 20 例患者：10 例患者 DAA 诱导的 SVR，10 例未治疗的对照组。所有患者均为新诊断的 BCLC 0/A 期 HCC。非肿瘤组织分析显示 DAA 治疗后干扰素相关基因（包括 MX1、ISG15 和 IFIT1）下调。两组之间的免疫谱/免疫细胞密度没有其他差异。DAA 治疗后发生的 HCC 的肿瘤内免疫谱在质量或数量上与未治疗患者的肿瘤无明显差异。
总之，基于 DAA 的治疗后 HCV 感染的清除仅导致发生 HCC 的肝硬化患者非肿瘤组织中干扰素刺激基因下调。肝免疫微环境的这些微小变化不太可能有利于 DAA 诱导 SVR 后 HCC 的发生或复发。
