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TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state
TGF-β induces senescence in embryonic tissues. Whether TGF-β in the hypoxic tumor microenvironment (TME) induces senescence in cancer and how the ensuing senescence-associated secretory phenotype (SASP) remodels the cellular TME to influence immune checkpoint inhibitor (ICI) responses are unknown. W...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187541/ https://www.ncbi.nlm.nih.gov/pubmed/36821441 http://dx.doi.org/10.1016/j.celrep.2023.112129 |
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author | Matsuda, Satoru Revandkar, Ajinkya Dubash, Taronish D. Ravi, Arvind Wittner, Ben S. Lin, Maoxuan Morris, Robert Burr, Risa Guo, Hongshan Seeger, Karsen Szabolcs, Annamaria Che, Dante Nieman, Linda Getz, Gad A. Ting, David T. Lawrence, Michael S. Gainor, Justin Haber, Daniel A. Maheswaran, Shyamala |
author_facet | Matsuda, Satoru Revandkar, Ajinkya Dubash, Taronish D. Ravi, Arvind Wittner, Ben S. Lin, Maoxuan Morris, Robert Burr, Risa Guo, Hongshan Seeger, Karsen Szabolcs, Annamaria Che, Dante Nieman, Linda Getz, Gad A. Ting, David T. Lawrence, Michael S. Gainor, Justin Haber, Daniel A. Maheswaran, Shyamala |
author_sort | Matsuda, Satoru |
collection | PubMed |
description | TGF-β induces senescence in embryonic tissues. Whether TGF-β in the hypoxic tumor microenvironment (TME) induces senescence in cancer and how the ensuing senescence-associated secretory phenotype (SASP) remodels the cellular TME to influence immune checkpoint inhibitor (ICI) responses are unknown. We show that TGF-β induces a deeper senescent state under hypoxia than under normoxia; deep senescence correlates with the degree of E2F suppression and is marked by multinucleation, reduced reentry into proliferation, and a distinct 14-gene SASP. Suppressing TGF-β signaling in tumors in an immunocompetent mouse lung cancer model abrogates endogenous senescent cells and suppresses the 14-gene SASP and immune infiltration. Untreated human lung cancers with a high 14-gene SASP display immunosuppressive immune infiltration. In a lung cancer clinical trial of ICIs, elevated 14-gene SASP is associated with increased senescence, TGF-β and hypoxia signaling, and poor progression-free survival. Thus, TME-induced senescence may represent a naturally occurring state in cancer, contributing to an immune-suppressive phenotype associated with immune therapy resistance. |
format | Online Article Text |
id | pubmed-10187541 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
record_format | MEDLINE/PubMed |
spelling | pubmed-101875412023-05-16 TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state Matsuda, Satoru Revandkar, Ajinkya Dubash, Taronish D. Ravi, Arvind Wittner, Ben S. Lin, Maoxuan Morris, Robert Burr, Risa Guo, Hongshan Seeger, Karsen Szabolcs, Annamaria Che, Dante Nieman, Linda Getz, Gad A. Ting, David T. Lawrence, Michael S. Gainor, Justin Haber, Daniel A. Maheswaran, Shyamala Cell Rep Article TGF-β induces senescence in embryonic tissues. Whether TGF-β in the hypoxic tumor microenvironment (TME) induces senescence in cancer and how the ensuing senescence-associated secretory phenotype (SASP) remodels the cellular TME to influence immune checkpoint inhibitor (ICI) responses are unknown. We show that TGF-β induces a deeper senescent state under hypoxia than under normoxia; deep senescence correlates with the degree of E2F suppression and is marked by multinucleation, reduced reentry into proliferation, and a distinct 14-gene SASP. Suppressing TGF-β signaling in tumors in an immunocompetent mouse lung cancer model abrogates endogenous senescent cells and suppresses the 14-gene SASP and immune infiltration. Untreated human lung cancers with a high 14-gene SASP display immunosuppressive immune infiltration. In a lung cancer clinical trial of ICIs, elevated 14-gene SASP is associated with increased senescence, TGF-β and hypoxia signaling, and poor progression-free survival. Thus, TME-induced senescence may represent a naturally occurring state in cancer, contributing to an immune-suppressive phenotype associated with immune therapy resistance. 2023-03-28 2023-02-22 /pmc/articles/PMC10187541/ /pubmed/36821441 http://dx.doi.org/10.1016/j.celrep.2023.112129 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Matsuda, Satoru Revandkar, Ajinkya Dubash, Taronish D. Ravi, Arvind Wittner, Ben S. Lin, Maoxuan Morris, Robert Burr, Risa Guo, Hongshan Seeger, Karsen Szabolcs, Annamaria Che, Dante Nieman, Linda Getz, Gad A. Ting, David T. Lawrence, Michael S. Gainor, Justin Haber, Daniel A. Maheswaran, Shyamala TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state |
title | TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state |
title_full | TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state |
title_fullStr | TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state |
title_full_unstemmed | TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state |
title_short | TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state |
title_sort | tgf-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187541/ https://www.ncbi.nlm.nih.gov/pubmed/36821441 http://dx.doi.org/10.1016/j.celrep.2023.112129 |
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