肿瘤微环境
生物
计算生物学
癌症研究
计算机科学
肿瘤细胞
作者
Elena Montauti,Samuel E. Weinberg,Peng Chu,Shuvam Chaudhuri,Nikita Mani,Radhika Iyer,Yuanzhang Zhou,Yusi Zhang,Changhong Liu,Xin Chen,Shana Gregory,Juncheng Wei,Yana Zhang,Wantao Chen,Zhaolin Sun,Ming Yan,Deyu Fang
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2022-11-23
卷期号:8 (47)
被引量:16
标识
DOI:10.1126/sciadv.abo4116
摘要
The tumor microenvironment (TME) enhances regulatory T (T reg ) cell stability and immunosuppressive functions through up-regulation of lineage transcription factor Foxp3, a phenomenon known as T reg fitness or adaptation. Here, we characterize previously unknown TME-specific cellular and molecular mechanisms underlying T reg fitness. We demonstrate that TME-specific stressors including transforming growth factor–β (TGF-β), hypoxia, and nutrient deprivation selectively induce two Foxp3-specific deubiquitinases, ubiquitin-specific peptidase 22 ( Usp22 ) and Usp21 , by regulating TGF-β, HIF, and mTOR signaling, respectively, to maintain T reg fitness. Simultaneous deletion of both USPs in T reg cells largely diminishes TME-induced Foxp3 up-regulation, alters T reg metabolic signatures, impairs T reg -suppressive function, and alleviates T reg suppression on cytotoxic CD8 + T cells. Furthermore, we developed the first Usp22 -specific small-molecule inhibitor, which dramatically reduced intratumoral T reg Foxp3 expression and consequently enhanced antitumor immunity. Our findings unveil previously unappreciated mechanisms underlying T reg fitness and identify Usp22 as an antitumor therapeutic target that inhibits T reg adaptability in the TME.
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