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

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

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

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.

Original language	English
Article number	147
Journal	Cell and Bioscience
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s13578-023-01090-8
Publication status	Published - Dec 2023

Keywords

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

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s13578-023-01090-8

Cite this

@article{b21466c4a5d5411185ab540c5d2b836c,

title = "Tumor-derived interleukin-1 receptor antagonist exhibits immunosuppressive functions and promotes pancreatic cancer",

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, interleukin-1 receptor antagonist, Pancreatic adenocarcinoma, Patient-derived xenograft, Tumor microenvironment",

author = "Fan, {Yu Ching} and Fong, {Yu Cin} and Kuo, {Chun Tse} and Li, {Chia Wei} and Chen, {Wei Yu} and Lin, {Jian Da} and Florian B{\"u}rtin and Michael Linnebacher and Bui, {Quoc Thang} and Lee, {Kuan Der} and Tsai, {Yuan Chin}",

note = "Funding Information: This research was funded by the Ministry of Science and Technology of Taiwan (grant nos. MOST109-2314-B-001-002-MY3 and MOST 109-2314-B-0001-008-MY3) and by Academia Sinica (AS-KPQ-111-KNT and AS-GC-110-05) to CWL. This research was also funded by the Ministry of Science and Technology of Taiwan (grant nos. MOST 110-2314-B-038-135-MY3) to YCT. Publisher Copyright: {\textcopyright} 2023, Society of Chinese Bioscientists in America (SCBA).",

year = "2023",

month = dec,

doi = "10.1186/s13578-023-01090-8",

language = "English",

volume = "13",

journal = "Cell and Bioscience",

issn = "2045-3701",

publisher = "Society of Chinese Bioscientists in America",

number = "1",

}

TY - JOUR

T1 - Tumor-derived interleukin-1 receptor antagonist exhibits immunosuppressive functions and promotes pancreatic cancer

AU - Fan, Yu Ching

AU - Fong, Yu Cin

AU - Kuo, Chun Tse

AU - Li, Chia Wei

AU - Chen, Wei Yu

AU - Lin, Jian Da

AU - Bürtin, Florian

AU - Linnebacher, Michael

AU - Bui, Quoc Thang

AU - Lee, Kuan Der

AU - Tsai, Yuan Chin

N1 - Funding Information: This research was funded by the Ministry of Science and Technology of Taiwan (grant nos. MOST109-2314-B-001-002-MY3 and MOST 109-2314-B-0001-008-MY3) and by Academia Sinica (AS-KPQ-111-KNT and AS-GC-110-05) to CWL. This research was also funded by the Ministry of Science and Technology of Taiwan (grant nos. MOST 110-2314-B-038-135-MY3) to YCT. Publisher Copyright: © 2023, Society of Chinese Bioscientists in America (SCBA).

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - IFN-γ

KW - Immunosuppression

KW - interleukin-1 receptor antagonist

KW - Pancreatic adenocarcinoma

KW - Patient-derived xenograft

KW - Tumor microenvironment

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UR - http://www.scopus.com/inward/citedby.url?scp=85168335471&partnerID=8YFLogxK

U2 - 10.1186/s13578-023-01090-8

DO - 10.1186/s13578-023-01090-8

M3 - Article

AN - SCOPUS:85168335471

SN - 2045-3701

VL - 13

JO - Cell and Bioscience

JF - Cell and Bioscience

IS - 1

M1 - 147

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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