Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells

  • Mol Cancer. 2024 May 8;23(1):95. doi: 10.1186/s12943-024-02001-2.
Ying Xie  #  1  2 ,  Yu Huang  #  1  2 ,  Zhi-Yong Li  #  1  2 ,  Weihua Jiang  1  2 ,  Nan-Xi Shi  1  2 ,  Yuanzhi Lu  3 ,  Guangchao Cao  1  2 ,  Zhinan Yin  4  5 ,  Xue-Jia Lin  6  7
Affiliations
  • 1. The Biomedical Translational Research Institute, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, School of Medicine, Jinan University, Guangzhou, 510632, China.
  • 2. 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.
  • 3. Department of Pathology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510632, China.
  • 4. The Biomedical Translational Research Institute, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, School of Medicine, Jinan University, Guangzhou, 510632, China. [email protected].
  • 5. 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. [email protected].
  • 6. The Biomedical Translational Research Institute, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, School of Medicine, Jinan University, Guangzhou, 510632, China. [email protected].
  • 7. 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. [email protected].
  • # Contributed equally.
PMID: 38720319 DOI: 10.1186/s12943-024-02001-2
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords
Cancer-promoting role; IL-21R; IgA+ B cell; MASH-driven HCC.
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