Tumor-derived interleukin-1 receptor antagonist exhibits immunosuppressive functions and promotes pancreatic cancer

  • Cell Biosci. 2023 Aug 10;13(1):147. doi: 10.1186/s13578-023-01090-8.
Yu-Ching Fan  1 ,  Yu-Cin Fong  2 ,  Chun-Tse Kuo  3 ,  Chia-Wei Li  3 ,  Wei-Yu Chen  4  5 ,  Jian-Da Lin  6  7 ,  Florian Bürtin  8 ,  Michael Linnebacher  9 ,  Quoc Thang Bui  10 ,  Kuan-Der Lee  10  11  12 ,  Yuan-Chin Tsai  13  14
Affiliations
  • 1. Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
  • 2. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 3. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  • 4. Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 5. Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 6. Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei City, 10617, Taiwan.
  • 7. Center for Computational and Systems Biology, National Taiwan University, Taipei City, 10617, Taiwan.
  • 8. Clinic of General Surgery, University Medical Center Rostock, Schillingallee 35, 18057, Rostock, Germany.
  • 9. Clinic of General Surgery, Molecular Oncology and Immunotherapy, University Medical Center Rostock, Schillingallee 69, 18057, Rostock, Germany.
  • 10. International Ph.D. Program for Cell Therapy and Regeneration Medicine (IPCTRM), School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 11. Department of Post-Baccalaureate Medicine, College of Medicine, Natioanl Chung Hsing University, Taichung, Taiwan.
  • 12. Cell Therapy and Regenerative Medicine Center and Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung, Taiwan.
  • 13. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 14. Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. [email protected].
PMID: 37563620 DOI: 10.1186/s13578-023-01090-8
Abstract

Background: Pancreatic ductal adenocarcinoma (PDA) is a pernicious disease characterized by an immunosuppressive milieu that is unresponsive to current immunotherapies. Interleukin-1 receptor antagonist (IL-1RA) is a natural anti-inflammatory cytokine; however, its contribution to Cancer pathogenesis and immunosuppression remains elusive. In this research, we investigated the role and mechanism of IL-1RA in malignant progression of PDA.

Results: Through analyzing clinical dataset and examining the pathological tumor tissues and serum samples, we have demonstrated that IL-1RA expression is elevated in human PDA and positively associated with malignant progression of PDA. To study the biological function of IL-1RA in tumors, we generated a set of mouse pancreatic Cancer cell lines with a knockout (KO) of the Il1rn gene, encoding IL-1RA, and compared the tumor growth rates in immune-competent and immune-deficient mice. We found that the Il1rn KO cells exhibited greater tumor inhibition in immune-competent mice, highlighting the crucial role of a functional immune system in Il1rn KO-mediated anti-tumor response. Consistently, we found an increase in CD8+ T cells and a decrease in CD11b+Ly6G- immunosuppressive mononuclear population in the tumor microenvironment of Il1rn KO-derived tumors. To monitor the inhibitory effects of IL-1RA on immune cells, we utilized a luciferase-based reporter CD4+ T cell line and splenocytes, which were derived from transgenic mice expressing ovalbumin-specific T cell receptors in CD8+ T cells, and mice immunized with ovalbumin. We showed that IL-1RA suppressed T cell receptor signaling and inhibited antigen-specific interferon-γ (IFN-γ) secretion and cytolytic activity in splenocytes.

Conclusions: Our findings illustrate the immunosuppressive properties of the natural anti-inflammatory cytokine IL-1RA, and provide a rationale for considering IL-1Ra-targeted therapies in the treatment of PDA.

Keywords
IFN-γ; Immunosuppression; Pancreatic adenocarcinoma; Patient-derived xenograft; Tumor microenvironment; interleukin-1 receptor antagonist.
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