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

Cell & Bioscience

Research

Michael Linnebacher¹  Florian Bürtin²  Jian-Da Lin³  Wei-Yu Chen⁴  Yu-Cin Fong⁵  Yuan-Chin Tsai⁶  Chun-Tse Kuo⁷  Chia-Wei Li⁷  Quoc Thang Bui⁸  Kuan-Der Lee⁹  Yu-Ching Fan^1,10 

[1] Clinic of General Surgery, Molecular Oncology and Immunotherapy, University Medical Center Rostock, Schillingallee 69, 18057, Rostock, Germany;Clinic of General Surgery, University Medical Center Rostock, Schillingallee 35, 18057, Rostock, Germany;Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, 10617, Taipei City, Taiwan;Center for Computational and Systems Biology, National Taiwan University, 10617, Taipei City, Taiwan;Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan;Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan;Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan;Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan;Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan;International Ph.D. Program for Cell Therapy and Regeneration Medicine (IPCTRM), School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;International Ph.D. Program for Cell Therapy and Regeneration Medicine (IPCTRM), School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;Department of Post-Baccalaureate Medicine, College of Medicine, Natioanl Chung Hsing University, Taichung, Taiwan;Cell Therapy and Regenerative Medicine Center and Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung, Taiwan;Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan;

关键词: Pancreatic adenocarcinoma;    interleukin-1 receptor antagonist;    Immunosuppression;    Tumor microenvironment;    IFN-γ;    Patient-derived xenograft;   

DOI  :  10.1186/s13578-023-01090-8

 received in 2023-04-21, accepted in 2023-07-19,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPancreatic 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.ResultsThrough 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© Society of Chinese Bioscientists in America (SCBA) 2023

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