Center for Molecular Medicine and Stem Cell Research, Faculty of Medicine, University of Kragujevac, Kragujevac, Serbia.
Eur J Immunol. 2011 Jul;41(7):1902-12. doi: 10.1002/eji.201141417.
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 CD27high CD11bhigh 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.
ST2 是白细胞介素-1 受体家族的成员，最近发现白细胞介素-33 是其天然配体。IL-33/ST2 途径在自身免疫和炎症条件下调节 Th1/Th2 免疫反应，但 ST2 信号在肿瘤生长和转移中的作用尚未得到研究。我们旨在研究 ST2 基因缺失是否会影响实验性转移性乳腺癌模型中的肿瘤发生、生长和转移以及抗肿瘤免疫。在携带乳腺癌的 BALB/c 小鼠中缺失 ST2 可减弱肿瘤生长和转移，同时血清中 IL-17、IFN-γ 和 TNF-α 的水平升高，IL-4 的水平降低。与 WT 受体相比，携带肿瘤的 ST2-/- 小鼠中激活的 CD27high CD11bhigh NK 细胞、CD69+和 KLRG- NK 细胞以及脾细胞、NK 细胞和 CD8+T 细胞的体外细胞毒性活性显著更高。与 WT 受体相比，在 ST2-/- 小鼠中发现表达 IFN-γ 的 NK 细胞数量显著增加。体内耗尽 CD8+或 NK 细胞表明 NK 细胞在 ST2-/- 小鼠中增强抗肿瘤免疫中起关键作用。我们首次报道，缺乏 ST2 的小鼠中乳腺癌进展和转移的抑制主要与 NK 细胞的细胞毒性活性增强以及系统 Th1/Th17 细胞因子增加有关。
