Tumor-Infiltrating Regulatory T Cell Accumulation in the Tumor Microenvironment is Mediated by IL33/ST2 Signaling

Regulatory T cells (Tregs) are enriched in the tumor microenvironment (TME) and suppress antitumor immunity. However, the molecular mechanism underlying the accumulation of Tregs in the TME are poorly understood. In various tumor models, tumor-infiltrating Tregs were highly enriched in TME and had significantly higher expression immune checkpoint molecules. To characterize tumor-infiltrating Tregs, we performed bulk RNA sequencing (RNA-seq) and found that proliferation-related genes, immune suppression-related genes, and cytokine/chemokine receptor genes were upregulated in tumor-infiltrating Tregs compared to tumor-infiltrating CD4+Foxp3− conventional T cells or splenic Tregs from the same tumor-bearing mice. Single-cell RNA sequencing and T-cell receptor sequencing also revealed active proliferation of tumor infiltrating Tregs by clonal expansion. One of these genes, ST2, an interleukin-33 (IL33) receptor, was identified as a potential factor driving Treg accumulation in the TME. Indeed, IL33-directed ST2 signaling induced the preferential proliferation of tumor infiltrating Tregs and enhanced tumor progression, whereas genetic deletion of ST2 in Tregs limited their TME accumulation and delayed tumor growth. These data demonstrated the IL33/ST2 axis in Tregs as one of the critical pathways for the preferential accumulation of Tregs in the TME and suggests that the IL33/ST2 axis may be a potential therapeutic target for cancer immunotherapy.