Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, Henan, China.
Faculty of Health Science, Nord University, Campus Levanger, Levanger, Norway.
Virchows Arch. 2019 Nov;475(5):579-586. doi: 10.1007/s00428-019-02579-9. Epub 2019 May 6.
Forkhead box p3 (Foxp3) regulatory T cells (Tregs) are abundant in the tumor microenvironment where they dampen functions of host anti-tumor immunity and promote cancer progression. Cytokine signaling is essential for the generation and function maintenance of Tregs in patients with cancers. Recent in vitro and in vivo studies have described that interleukin (IL)-33 plays a critical role in regulating the expansion and function of Tregs. However, the regulatory role of IL-33 in Treg recruitment within the microenvironment of human esophageal squamous cell carcinoma (ESCC) to date is poorly understood. In this study, we have therefore characterized the expression of IL-33 by immunohistochemistry (IHC) and double immunofluorescence staining and analyzed its relationship with FoxP3 Treg accumulation in the microenvironment in 80 patients with ESCC. IHC observation revealed a high expression level of IL-33 in both ESCC mass and stroma, which paralleled to a high density of FoxP3 Tregs accumulated in the same compartments. Statistical analysis showed that the scores for cell densities of tumor- and stroma-expressing IL-33 were significantly correlated with the scores for density of FoxP3 Tregs in the tumor stroma. Further immunofluorescence images demonstrated that IL-33 functional receptor, ST2, was preferentially expressed in FoxP3 Tregs, suggesting a possible effecting pathway for IL-33. In addition, cyclooxygenase-2, one of the important immunosuppressive factors, was highly illustrated in FoxP3 Tregs. We have therefore concluded that microenvironmental-expressing IL-33 is associated with the recruitment of Tregs in human ESCCs.
叉头框蛋白 P3（Foxp3）调节性 T 细胞（Tregs）在肿瘤微环境中丰富存在，它们抑制宿主抗肿瘤免疫功能并促进癌症进展。细胞因子信号对于癌症患者 Tregs 的产生和功能维持至关重要。最近的体外和体内研究表明，白细胞介素（IL）-33 在调节 Tregs 的扩增和功能方面发挥着关键作用。然而，迄今为止，IL-33 在人食管鳞状细胞癌（ESCC）微环境中调节 Treg 募集的调节作用仍知之甚少。在这项研究中，我们通过免疫组织化学（IHC）和双重免疫荧光染色对 IL-33 的表达进行了特征描述，并分析了其与 FoxP3 Treg 在 80 例 ESCC 患者微环境中积累的关系。IHC 观察显示，IL-33 在 ESCC 肿块和基质中均呈高表达，与在同一部位积聚的 FoxP3 Treg 的高密度平行。统计分析显示，肿瘤和基质表达的细胞密度评分与肿瘤基质中 FoxP3 Treg 的密度评分显著相关。进一步的免疫荧光图像表明，IL-33 功能性受体 ST2 优先在 FoxP3 Tregs 中表达，提示 IL-33 可能存在作用途径。此外，环氧化酶-2 是一种重要的免疫抑制因子，在 FoxP3 Tregs 中高度表达。因此，我们得出结论，微环境中表达的 IL-33 与人类 ESCC 中 Treg 的募集有关。
