Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Cancer Immunol Res. 2023 May 3;11(5):687-702. doi: 10.1158/2326-6066.CIR-22-0426.
The tumor immune microenvironment dynamically evolves to support tumor growth and progression. Immunosuppressive regulatory T cells (Treg) promote tumor growth and metastatic seeding in patients with breast cancer. Deregulation of plasticity between Treg and Th17 cells creates an immune regulatory framework that enables tumor progression. Here, we discovered a functional role for Hedgehog (Hh) signaling in promoting Treg differentiation and immunosuppressive activity, and when Hh activity was inhibited, Tregs adopted a Th17-like phenotype complemented by an enhanced inflammatory profile. Mechanistically, Hh signaling promoted O-GlcNAc modifications of critical Treg and Th17 transcription factors, Foxp3 and STAT3, respectively, that orchestrated this transition. Blocking Hh reprogramed Tregs metabolically, dampened their immunosuppressive activity, and supported their transdifferentiation into inflammatory Th17 cells that enhanced the recruitment of cytotoxic CD8+ T cells into tumors. Our results demonstrate a previously unknown role for Hh signaling in the regulation of Treg differentiation and activity and the switch between Tregs and Th17 cells in the tumor microenvironment.
肿瘤免疫微环境动态演变以支持肿瘤生长和进展。在乳腺癌患者中，抑制性调节性 T 细胞（Treg）促进肿瘤生长和转移播种。Treg 和 Th17 细胞之间可塑性的失调会产生免疫调节框架，从而促进肿瘤进展。在这里，我们发现 Hedgehog（Hh）信号在促进 Treg 分化和免疫抑制活性方面具有功能作用，当 Hh 活性受到抑制时，Tregs 会采用 Th17 样表型，并伴有增强的炎症特征。从机制上讲，Hh 信号促进了关键的 Treg 和 Th17 转录因子 Foxp3 和 STAT3 的 O-GlcNAc 修饰，分别协调了这种转变。阻断 Hh 信号会重塑 Treg 的代谢，抑制其免疫抑制活性，并支持它们向炎症性 Th17 细胞的转分化，从而增强细胞毒性 CD8+T 细胞向肿瘤的募集。我们的结果表明，Hh 信号在调节 Treg 分化和活性以及肿瘤微环境中 Tregs 和 Th17 细胞之间的转换方面具有先前未知的作用。
