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

Yu-Ching Fan; Yu-Cin Fong; Chun-Tse Kuo; Chia-Wei Li; Wei-Yu Chen; Jian-Da Lin; Florian Bürtin; Michael Linnebacher; Quoc Thang Bui; Kuan-Der Lee; Yuan-Chin Tsai

doi:10.1186/s13578-023-01090-8

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.

Authors

Yu-Ching Fan¹, Yu-Cin Fong², Chun-Tse Kuo³, Chia-Wei Li³, Wei-Yu Chen^{4

5}, Jian-Da Lin^{6

7}, Florian Bürtin⁸, Michael Linnebacher⁹, Quoc Thang Bui¹⁰, 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. yuanchin@tmu.edu.tw.
¹⁴ Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. yuanchin@tmu.edu.tw.

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.

Abstract

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