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.