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IL-33 signaling alters regulatory T cell diversity in support of tumor development [2018]

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

ORGANISM(S): Mus musculus

PROVIDER: GSE139229 | GEO | 2019/12/03

REPOSITORIES: GEO

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IL-33 signaling alters regulatory T cell diversity in support of tumor development

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

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IL-33 signaling alters regulatory T cell diversity in support of tumor development

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

Project description:Regulatory T cells (Tregs) are enriched in the tumor microenvironment (TME) and suppress anti-tumor immunity. However, the origin of tumor-infiltrating (TI) Tregs and the molecular mechanism underlying their TME accumulation are poorly understood. Although IL-33 was reported to regulate the expansion and function of Tregs, its direct role on TI Tregs and its contribution to tumor progression remain uncertain. Firstly, we demonstrated TI Tregs were primarily thymus-derived. More importantly, we found using comparative transcriptome analysis that proliferation-related genes were prominently upregulated in TI Tregs compared with TI CD4+Foxp3− conventional T cells or splenic Tregs of same tumor-bearing mice. One of these genes, ST2, an interleukin-33 (IL-33) receptor, was identified as a potential factor driving Treg accumulation in the TME. Indeed, IL-33-directed ST2 signaling induced the preferential proliferation of TI Tregs and enhanced tumor progression, while genetic deletion of ST2 in Tregs limited their TME accumulation and delayed tumor growth. These data demonstrate the IL-33/ST2 axis in Tregs as one of the critical pathways for the preferential accumulation of thymus-derived Tregs in the TME and suggest the axis as a potential therapeutic target for cancer immunotherapy.

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