Longitudinal single cell profiling of regulatory T cells identifies IL-33 as a driver of tumor immunosuppression

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 used single cell RNA-Seq to longitudinally profile conventional CD4 + T cells (T conv ) and T regs in a genetic mouse model of lung adenocarcinoma. Tissue-infiltrating and peripheral CD4 + T cells differed, highlighting divergent pathways of activation during tumorigenesis. Longitudinal shifts in T reg heterogeneity suggested increased terminal differentiation and stabilization of an effector phenotype over time. In particular, effector T regs had enhanced expression of the interleukin 33 receptor ST2. T reg -specific deletion of ST2 reduced effector T regs , increased infiltration of CD8 + T cells into tumors, and decreased tumor burden. Our study shows that ST2 plays a critical role in T reg -mediated immunosuppression in cancer, highlighting new potential paths for therapeutic intervention.