Longitudinal Single Cell Profiling of Regulatory T Cells Identifies IL-33 as a Driver of Tumor Immunosuppression

Abstract

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_regs heterogeneity suggested stabilization of a specialized effector phenotype over time that had enhanced expression of the interleukin 33 receptor ST2. T_regs-specific deletion of ST2 altered lung effector T_regs diversity, increased infiltration of CD8⁺ T cells into tumors, and decreased tumor burden. Our study shows that ST2 plays a critical role in T_regs-mediated immunosuppression in cancer, highlighting new potential paths for therapeutic intervention.