IL-33 in the tumor microenvironment is associated with the accumulation of FoxP3-positive regulatory T cells in human esophageal carcinomas

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.