IL-33 Signaling Alters Regulatory T Cell Diversity in Support of Tumor Development

Regulatory T cells (T_regs) can impair anti-tumor immune responses and are associated with poor prognosis in multiple cancer types. T_regs in human tumors span diverse transcriptional states distinct from those of peripheral T_regs, but their contribution to tumor development remains unknown. Here, we use single-cell RNA sequencing (RNA-seq) to longitudinally profile dynamic shifts in the distribution of T_regs in a genetically engineered mouse model of lung adenocarcinoma. In this model, interferon-responsive T_regs are more prevalent early in tumor development, whereas a specialized effector phenotype characterized by enhanced expression of the interleukin-33 receptor ST2 is predominant in advanced disease. T_reg-specific deletion of ST2 alters the evolution of effector T_reg diversity, increases infiltration of CD8⁺ T cells into tumors, and decreases tumor burden. Our study shows that ST2 plays a critical role in T_reg-mediated immunosuppression in cancer, highlighting potential paths for therapeutic intervention.