Matsuura Ryuma, Punyawatthananukool Siwakorn, Kawakami Ryoji, Mikami Norihisa, Sakaguchi Shimon, Narumiya Shuh
Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Department of Experimental Pathology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Proc Natl Acad Sci U S A. 2025 Dec 9;122(49):e2424251122. doi: 10.1073/pnas.2424251122. Epub 2025 Dec 4.
Foxp3 regulatory T cells (Tregs) heavily infiltrate malignant tumors and restrict antitumor immunity. These tumor-infiltrating Tregs (TI-Tregs) adopt a distinct phenotype by expressing a unique set of genes. This TI-Treg gene expression signature is conserved in TI-Tregs across species and tumor types and stages, suggesting the presence of a common inducing mechanism in the tumor microenvironment (TME). However, identity of such a mechanism remains elusive. Here, we show that prostaglandin E (PGE) produced in TME directly acts on its receptor EP2/EP4 on Tregs to induce the TI-Treg phenotype. PGE added to TCR-activated Tregs induces a set of genes, many of which are included in the TI-Treg signature, in both induced Tregs (iTregs) and naturally occurring Tregs (nTregs) via EP2/EP4- cAMP-PKA pathway. Concomitantly, PGE-treated Tregs exhibit potent suppressive activity to CD8 T cells and strongly inhibit their proliferation in an EP4 dependent manner. Consistently, selective loss of EP2 and EP4 in mouse Tregs reduces expression of those genes in Tregs infiltrating Lewis lung carcinoma 1 (LLC1) mouse tumor and significantly delays the tumor progression. In human FOXP3iTregs, PGE-EP4 signaling upregulated the expression of Treg signature genes, FOXP3, CD25, and CTLA-4 as well as a typical TI-Treg signature gene, 4-1BB, and enhanced suppressive activity. Furthermore, analysis of single-cell RNA sequencing of nasopharyngeal cancer patients demonstrates preferential expression of the TI-Treg signature genes in Tregs infiltrating the tumor group compared to the tumor group. These findings suggest that PGE-EP2/EP4 signaling is one of the core mechanisms inducing the TI-Treg phenotype in TME for tumor growth.
叉头框蛋白3调节性T细胞（Tregs）大量浸润恶性肿瘤并抑制抗肿瘤免疫。这些肿瘤浸润性Tregs（TI-Tregs）通过表达一组独特的基因呈现出独特的表型。这种TI-Treg基因表达特征在跨物种、肿瘤类型和阶段的TI-Tregs中是保守的，这表明肿瘤微环境（TME）中存在一种共同的诱导机制。然而，这种机制的具体身份仍然难以捉摸。在这里，我们表明TME中产生的前列腺素E（PGE）直接作用于Tregs上的受体EP2/EP4，以诱导TI-Treg表型。添加到经TCR激活的Tregs中的PGE通过EP2/EP4 - cAMP - PKA途径在诱导性Tregs（iTregs）和天然存在的Tregs（nTregs）中诱导一组基因，其中许多基因包含在TI-Treg特征中。同时，经PGE处理的Tregs对CD8 T细胞表现出强大的抑制活性，并以EP4依赖的方式强烈抑制其增殖。一致地，小鼠Tregs中EP2和EP4的选择性缺失降低了浸润Lewis肺癌1（LLC1）小鼠肿瘤的Tregs中这些基因的表达，并显著延迟了肿瘤进展。在人FOXP3 iTregs中，PGE - EP4信号上调了Treg特征基因、FOXP3、CD25和CTLA - 4以及典型的TI-Treg特征基因4 - 1BB的表达，并增强了抑制活性。此外，对鼻咽癌患者的单细胞RNA测序分析表明，与非肿瘤组相比，肿瘤浸润组的Tregs中TI-Treg特征基因的表达更为优先。这些发现表明，PGE - EP2/EP4信号是TME中诱导TI-Treg表型以促进肿瘤生长的核心机制之一。
