The Biomedical Translational Research Institute, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, School of Medicine, Jinan University, Guangzhou, 510632, China.
Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated With Jinan University, Jinan University, Zhuhai, 519000, China.
Mol Cancer. 2024 May 8;23(1):95. doi: 10.1186/s12943-024-02001-2.
Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC.
The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA B cells.
HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8 T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA B cells.
IL-21R plays a cancer-promoting role by inducing IgA B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.
免疫监视失调与代谢相关脂肪性肝炎（MASH）驱动的肝细胞癌（HCC）的发展密切相关；然而，其潜在机制尚不清楚。在此，我们旨在确定白细胞介素 21 受体（IL-21R）在 MASH 驱动的 HCC 中的作用。
使用免疫组织化学染色评估人 HCC 标本中 IL-21R 的临床意义。此外，在 STAM 模型中评估了小鼠中 IL-21R 的表达。此后，在 IL-21R 缺陷小鼠和野生型对照小鼠之间应用两种不同的 MASH 驱动的 HCC 小鼠模型，以探讨 IL-21R 在 MASH 驱动的 HCC 中的作用。为了进一步阐明 IL-21R 影响 MASH 驱动的 HCC 的潜在机制，进行了全转录组测序、流式细胞术和过继性淋巴细胞转移。最后，通过流式细胞术、酶联免疫吸附测定、免疫荧光染色、染色质免疫沉淀测定和 Western blot 分析，探讨了 IL-21R 诱导 IgA B 细胞的机制。
IL-21R 高表达的 HCC 患者无复发生存期较差、TNM 分期较晚且脂肪变性严重。此外，在小鼠肝肿瘤中发现 IL-21R 上调。特别地，由于免疫抑制性 IgA B 细胞减少，IL-21R 的缺失阻碍了 MASH 驱动的肝癌发生，脂质积累显著减少。此外，由于抑制性 IgA B 细胞减少，IL-21R 缺失导致细胞毒性 CD8 T 淋巴细胞激活增强。机制上，在 MASH 驱动的 HCC 中激活了 IL-21R-STAT1-c-Jun/c-Fos 调节轴，从而促进了 Igha 的转录，导致 IgA B 细胞的诱导。
IL-21R 通过在 MASH 驱动的肝癌发生中诱导 IgA B 细胞发挥致癌作用。靶向 IL-21R 信号代表了癌症治疗的一种潜在治疗策略。
