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

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-? (IFN-?) 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.

Automated summary

In this study, researchers found that IL-1Ra expression is elevated in human pancreatic ductal adenocarcinoma (PDA) and positively associated with its malignant progression. Further experiments demonstrated that IL-1Ra inhibits tumor growth in immune-competent mice by regulating immune cell activity. These findings suggest that IL-1Ra-targeted therapies could be a potential treatment for PDA.