Increased expression of ST2 on regulatory T cells is associated with cancer associated fibroblast-derived IL-33 in laryngeal cancer

Interleukin (IL)− 33 plays an essential role in regulatory T cell (Treg)-mediated immunosuppression in cancers and underlies the crosstalk between Tregs and the tumor microenvironment . However, the phenotypic characteristics of subset Tregs modulated by IL-33 and its association with the tumor microenvironment are not fully understood. This study aimed to examine the expression of ST2, the receptor of IL-33, on Tregs in tumors and to evaluate their association with cancer associated fibroblasts (CAFs) and reciprocal influences on the prognosis of laryngeal cancer . Our results showed that increased numbers of Tregs were found in laryngeal tumor tissues. Tregs in stromal IL-33-positive tumor tissues demonstrated significantly higher expression of ST2 than those in IL-33 - or adjacent nontumor tissues. ST2-expressing Tregs exhibited upregulation of Ki67 and CTLA4 compared with their ST2 - negative counterparts. Furthermore, IL-33 in the tumor microenvironment was mainly derived from fibroblasts. ST2 expression on Tregs was correlated with the number of IL-33-positive CAFs. High ST2 expression on Tregs, combined high ST2 on Tregs and the presence of IL-33 expressing CAFs was associated with worse survival outcomes in laryngeal cancer. This study indicated that increased expression of ST2 on Tregs is associated with microenvironmental IL-33 signaling derived from CAFs in laryngeal cancer, unraveling the special role of Tregs and fibroblasts in modulating IL-33/ST2 involved immune-evasive tumor microenvironment.