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A deubiquitination module essential for T(reg) fitness in the tumor microenvironment
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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699683/ https://www.ncbi.nlm.nih.gov/pubmed/36427305 http://dx.doi.org/10.1126/sciadv.abo4116 |
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author | Montauti, Elena Weinberg, Samuel E. Chu, Peng Chaudhuri, Shuvam Mani, Nikita L. Iyer, Radhika Zhou, Yuanzhang Zhang, Yusi Liu, Changhong Xin, Chen Gregory, Shana Wei, Juncheng Zhang, Yana Chen, Wantao Sun, Zhaolin Yan, Ming Fang, Deyu |
author_facet | Montauti, Elena Weinberg, Samuel E. Chu, Peng Chaudhuri, Shuvam Mani, Nikita L. Iyer, Radhika Zhou, Yuanzhang Zhang, Yusi Liu, Changhong Xin, Chen Gregory, Shana Wei, Juncheng Zhang, Yana Chen, Wantao Sun, Zhaolin Yan, Ming Fang, Deyu |
author_sort | Montauti, Elena |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9699683 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-96996832022-12-05 A deubiquitination module essential for T(reg) fitness in the tumor microenvironment Montauti, Elena Weinberg, Samuel E. Chu, Peng Chaudhuri, Shuvam Mani, Nikita L. Iyer, Radhika Zhou, Yuanzhang Zhang, Yusi Liu, Changhong Xin, Chen Gregory, Shana Wei, Juncheng Zhang, Yana Chen, Wantao Sun, Zhaolin Yan, Ming Fang, Deyu Sci Adv Biomedicine and Life Sciences 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. American Association for the Advancement of Science 2022-11-25 /pmc/articles/PMC9699683/ /pubmed/36427305 http://dx.doi.org/10.1126/sciadv.abo4116 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Montauti, Elena Weinberg, Samuel E. Chu, Peng Chaudhuri, Shuvam Mani, Nikita L. Iyer, Radhika Zhou, Yuanzhang Zhang, Yusi Liu, Changhong Xin, Chen Gregory, Shana Wei, Juncheng Zhang, Yana Chen, Wantao Sun, Zhaolin Yan, Ming Fang, Deyu A deubiquitination module essential for T(reg) fitness in the tumor microenvironment |
title | A deubiquitination module essential for T(reg) fitness in the tumor microenvironment |
title_full | A deubiquitination module essential for T(reg) fitness in the tumor microenvironment |
title_fullStr | A deubiquitination module essential for T(reg) fitness in the tumor microenvironment |
title_full_unstemmed | A deubiquitination module essential for T(reg) fitness in the tumor microenvironment |
title_short | A deubiquitination module essential for T(reg) fitness in the tumor microenvironment |
title_sort | deubiquitination module essential for t(reg) fitness in the tumor microenvironment |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699683/ https://www.ncbi.nlm.nih.gov/pubmed/36427305 http://dx.doi.org/10.1126/sciadv.abo4116 |
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