Dataset Information

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.

SUBMITTER: Fan YC

PROVIDER: S-EPMC10416534 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Fan Yu-Ching YC Fong Yu-Cin YC Kuo Chun-Tse CT Li Chia-Wei CW Chen Wei-Yu WY Lin Jian-Da JD Bürtin Florian F Linnebacher Michael M Bui Quoc Thang QT Lee Kuan-Der KD Tsai Yuan-Chin YC

Cell & bioscience 20230810 1

<h4>Background</h4>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.<h4>Results</h4>Through analyzing clinical dataset an ...[more]

PMID: 37563620

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Project description:BackgroundProinflammatory interleukin-33 (IL-33) binds to its receptor ST2L and is involved in inflammation and the malignant behavior of cancer cells. However, the role of IL-33-ST2L and the IL-33 decoy receptor sST2 in the tumor microenvironment of pancreatic cancer is unclear. Because we previously reported that sST2 derived from colon cancer cells profoundly influences malignant tumor growth, we hypothesized that sST2 released from pancreatic cancer cells also modulates IL-33-ST2L signaling in the tumor microenvironment, thereby influencing tumor growth.MethodsST2 (ST2L and sST2) expression in mouse pancreatic cancer Panc02 cells was downregulated by shRNAs. mRNA expression levels of IL-33, ST2, cytokines and chemokines in the cells and tumor tissues were examined using real-time PCR. sST2 secretion and the amount of CXCL3 in tumor tissues were measured using ELISA. Tumor growth was investigated after injection of the cells into the pancreas of C57BL/6 mice. MPO+, F4/80+ and CD20+ cells in tumor tissues were detected using immunohistochemistry.ResultsSome but not all human and mouse pancreatic cancer cell lines preferentially expressed sST2. Then, we investigated the role of sST2 in orthotopic tumor growth of sST2-expressing mouse pancreatic cancer Panc02 cells in immunocompetent mice. shRNA-mediated knockdown of sST2 expression in the cells suppressed orthotopic tumor growth, which was partially recovered by overexpression of shRNA-resistant sST2 mRNA but was not evident in IL-33 knockout mice. This was associated with decreases in Cxcl3 expression, vessel density and accumulation of cancer-associated neutrophils but not cancer-associated macrophages. Administration of SB225002, an inhibitor of the CXCL3 receptor CXCR2, induced similar effects.ConclusionsCancer cell-derived sST2 enhances tumor growth through upregulation of CXCL3 via inhibition of IL-33-ST2L signaling in the tumor microenvironment of pancreatic cancer. These results suggest that the sST2 and the CXCL3-CXCR2 axis could be therapeutic targets.

Dataset Information

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

Background

Results

Conclusions

Publications

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

Similar Datasets

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