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

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

Journal

Cell & bioscience
ISSN: 2045-3701
Titre abrégé: Cell Biosci
Pays: England
ID NLM: 101561195

Informations de publication

Date de publication:
10 Aug 2023
Historique:
received: 21 04 2023
accepted: 19 07 2023
medline: 11 8 2023
pubmed: 11 8 2023
entrez: 10 8 2023
Statut: epublish

Résumé

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. 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 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.

Sections du résumé

BACKGROUND 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 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
CONCLUSIONS 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.

Identifiants

DOI: 10.1186/s13578-023-01090-8 PMID: 37563620 PMC: PMC10416534
pubmed: 37563620
doi: 10.1186/s13578-023-01090-8
pii: 10.1186/s13578-023-01090-8
pmc: PMC10416534
doi:

Types de publication

Journal Article

Langues

eng

Pagination

147

Subventions

Organisme : Ministry of Science and Technology, Taiwan
ID : MOST109-2314-B-001-002-MY3
Organisme : Ministry of Science and Technology, Taiwan
ID : MOST 109-2314-B-0001-008-MY3
Organisme : Ministry of Science and Technology, Taiwan
ID : MOST 110-2314-B-038-135-MY3
Organisme : Academia Sinica
ID : AS-KPQ-111-KNT
Organisme : Academia Sinica
ID : AS-GC-110-05

Informations de copyright

© 2023. Society of Chinese Bioscientists in America (SCBA).

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Auteurs

Yu-Ching Fan (YC)

Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.

Yu-Cin Fong (YC)

Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

Chun-Tse Kuo (CT)

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Chia-Wei Li (CW)

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Wei-Yu Chen (WY)

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.

Jian-Da Lin (JD)

Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei City, 10617, Taiwan.
Center for Computational and Systems Biology, National Taiwan University, Taipei City, 10617, Taiwan.

Florian Bürtin (F)

Clinic of General Surgery, University Medical Center Rostock, Schillingallee 35, 18057, Rostock, Germany.

Michael Linnebacher (M)

Clinic of General Surgery, Molecular Oncology and Immunotherapy, University Medical Center Rostock, Schillingallee 69, 18057, Rostock, Germany.

Quoc Thang Bui (QT)

International Ph.D. Program for Cell Therapy and Regeneration Medicine (IPCTRM), School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Kuan-Der Lee (KD)

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.

Yuan-Chin Tsai (YC)

Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. yuanchin@tmu.edu.tw.
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.
ORCID: 0000-0003-3264-3513

Classifications MeSH