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Prostaglandin E2-EP2/EP4 signaling induces the tumor-infiltrating Treg phenotype for tumor growth

ABSTRACT: Foxp3+ regulatory T cells (Tregs) heavily infiltrate malignant tumors and restrict anti-tumor immunity. These tumor-infiltrating Tregs (TI-Tregs) adopt a distinct phenotype by expressing a unique set of genes including those encoding various co-stimulatory and co-inhibitory molecules. This TI-Treg gene expression signature is conserved in TI-Tregs across species and the types and stages of tumors, suggesting the presence of a common inducing mechanism or mechanisms in tumor microenvironment (TME). However, identity of such a mechanism remains elusive. Here, we show that prostaglandin E2 (PGE2) produced in TME directly acts on its receptor EP2/EP4 on Tregs to induce the TI-Treg phenotype. Indeed, PGE2 added to TCR-activated Tregs induces a set of genes, many of which are included in the reported TI-Treg signature genes, in both induced Tregs (iTregs) and naturally occurring Tregs (nTregs), in a manner dependent on EP2 and EP4 via cAMP-PKA pathway. This is not limited to phenotypic changes, as EP4 agonist-treated Tregs exhibit potent suppressive activity to CD8+ T cells and strongly inhibit their proliferation and survival. Consistently, selective loss of EP2 and EP4 in mouse Tregs and pharmacological inhibition of EP2 and EP4 reduce expression of those genes in Tregs infiltrating LLC1 mouse syngeneic tumor, and significantly delay the tumor progression. In human FOXP3+iTregs, the expression of Treg signature genes, FOXP3, CD25 and CTLA4 as well as a typical TI-Treg signature gene, 4-1BB are significantly upregulated by PGE2-EP4 signaling. Furthermore, analysis of scRNA-seq of nasopharyngeal cancer patients demonstrates preferential expression of the TI-Treg signature genes in Tregs infiltrating the PTGShi tumor group compared to the PTGS2lo tumor group. These findings suggest that PGE2-EP2/EP4 signaling is one of the molecular mechanisms inducing the TI-Treg phenotype in TME.

ORGANISM(S): Mus musculus

PROVIDER: GSE282089 | GEO | 2025/11/24

REPOSITORIES: GEO

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Project description:Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/protein acetyltransferases and histone/protein deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4-6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs. RNA was isolated using RNeasy kits (QIAGEN), and RNA integrity and quantity were analyzed by NanoDrop ND-1000 and Nanochip 2100 Bioanalyzer (Agilent Technologies). Microarray experiments were performed using whole mouse genome oligoarrays (Mouse430a, Affymetrix) and array data analyzed using MAYDAY 2.12 software. Array data were subjected to robust multiarray average (RMA) normalization and analyzed using Student’s t test. Only data with a false discovery rate-adjusted P value of less than 0.05 and at least 2× differential expression were included in the analysis. Data underwent z-score transformation for display.

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Prostaglandin E2-EP2/EP4 signaling induces the tumor-infiltrating Treg phenotype for tumor growth

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