Abstract
ST2 is a member of the IL-1 receptor family and IL-33 was recently identified as its natural ligand. The IL-33/ST2 pathway regulates Th1/Th2 immune responses in autoimmune and inflammatory conditions, but the role of ST2 signaling in tumor growth and metastasis has not been investigated. We aimed to investigate whether ST2 gene deletion affects tumor appearance, growth, and metastasis, and antitumor immunity in an experimental metastatic breast cancer model. Deletion of ST2 in BALB/c mice bearing mammary carcinoma attenuated tumor growth and metastasis, which was accompanied by increased serum levels of IL-17, IFN-γ, and TNF-α and decreased IL-4. Tumor-bearing ST2−/− mice had significantly higher percentages of activated CD27highCD11bhigh NK cells, CD69+ and KLRG− NK cells and higher cytotoxic activity of splenocytes, NK cells, and CD8+ T cells in vitro. A significantly higher number of NK cells expressing IFN-γ were found in ST2−/− mice compared with WT recipients. In vivo depletion of CD8+ or NK cells revealed a key role for NK cells in enhanced antitumor immunity in ST2−/− mice. We report for the first time that suppressed breast cancer progression and metastasis in mice lacking ST2 corresponds mainly with enhanced cytotoxic activity of NK cells, and increased systemic Th1/Th17 cytokines.
Highlights
The ST2 gene, called T1, DER-4 and Fit-1, is a member of the interleukin-1 receptor (IL-1R) family that was originally identified in oncogene- or serum-stimulated fibroblasts [1, 2]
Abs against ST2, ST2-Fc fusion proteins or use of ST2-deficient mice in various pathological conditions revealed that lack of IL-33/ST2 signaling favors the expansion of Th1/Th17 cells and inhibits Th2 cell-mediated immune responses [3, 5, 28, 31]
ST2-defficient mice show delayed mammary tumor appearance, slower tumor growth, and progression delayed in ST2À/À compared with WT mice
Summary
The ST2 gene, called T1, DER-4 and Fit-1, is a member of the interleukin-1 receptor (IL-1R) family that was originally identified in oncogene- or serum-stimulated fibroblasts [1, 2]. Cellular immune response 1903 atherosclerosis, and obesity, but it can enhance Th2 and mast cell-mediated diseases such as asthma and anaphylaxis. Breast cancer is one of the leading causes of cancer deaths among women worldwide [18]. The initiation of breast cancer might be caused by a combination of oncogenic mutations that promote genetic instability and accelerated cellular proliferation [19]. The major cause of breast cancer deaths is the development of distant organ metastasis in lungs, bones, liver, and brain [20]. Antitumor immune responses are neither potent nor effective [21]
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