Intratumoral IL-33+CD4+FoxP3+ regulatory T cell infiltration determines poor clinical outcomes and intensive immunoevasive contexture in patients with pancreatic cancer after surgical resection: a cohort study
Ning Pu, Qiangda Chen, Jiande Han, Zhihang Xu, Zhenlai Jiang, Taochen He, Yanfei An, Yaolin Xu, Wei Gan, Haibo Wang, Wenquan Wang, Wenchuan Wu, Yun Jin, Jun Yu, Wenhui Lou, Hanlin Yin, Liang Liu
Abstract
BACKGROUND: Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is constitutively expressed in barrier cells such as endothelial cells and fibroblasts. While the expression of IL-33 in regulatory T cells (Tregs) has been previously reported, its clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study aims to investigate the clinical relevance and biological role of IL-33 + Tregs in PDAC. METHODS: Infiltration of IL-33 + Tregs was assessed by immunohistochemistry in 215 patients from our institute. The correlation between IL-33 + Tregs and clinical characteristics was analyzed. Additionally, the functional status of cytotoxic T cells in relation to IL-33 + Treg infiltration was examined. The impact of IL-33 + Tregs on the tumor microenvironment (TME) was further evaluated both in silico and in vitro . RESULTS: IL-33 + Tregs infiltration was confirmed in PDAC tissues, and its abundance was positively associated with microvascular invasion, perineural invasion, and elevated serum CA19-9 levels. Patients with higher tumor-infiltrating IL-33 + Tregs demonstrated poorer overall survival (OS) and recurrence-free survival (RFS) compared to those with lower infiltration levels. Multivariate analysis confirmed IL-33 + Tregs as an independent prognostic factor for both OS and RFS, with improved survival prediction when combined with tumor differentiation. Subgroup analyses indicated that serum CA19-9 was not a useful risk stratification tool in patients with high IL-33 + Treg infiltration, and these patients showed limited survival benefit from adjuvant chemotherapy. Furthermore, increased IL-33 + Treg infiltration was associated with more pronounced immunosuppressive TME, marked by a reduction in cytotoxic phenotypes and an upregulation of exhausted markers on CD8 + T cells. CONCLUSION: Our findings identify IL-33 + Tregs as a novel subtype of Tregs, with strong prognostic value for survival risk stratification and therapeutic response prediction in PDAC. IL-33 + Tregs exhibit more pronounced immunosuppressive capabilities, impairing CD8 + T cell function. With further investigation, IL-33 + Tregs may represent a promising immunotherapeutic target for PDAC.