Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
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
_version_ 1784839134425120768
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
work_keys_str_mv AT montautielena adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT weinbergsamuele adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT chupeng adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT chaudhurishuvam adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT maninikital adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT iyerradhika adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT zhouyuanzhang adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT zhangyusi adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT liuchanghong adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT xinchen adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT gregoryshana adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT weijuncheng adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT zhangyana adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT chenwantao adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT sunzhaolin adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT yanming adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT fangdeyu adeubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT montautielena deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT weinbergsamuele deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT chupeng deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT chaudhurishuvam deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT maninikital deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT iyerradhika deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT zhouyuanzhang deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT zhangyusi deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT liuchanghong deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT xinchen deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT gregoryshana deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT weijuncheng deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT zhangyana deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT chenwantao deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT sunzhaolin deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT yanming deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment
AT fangdeyu deubiquitinationmoduleessentialfortregfitnessinthetumormicroenvironment