TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state
Summary: 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 u...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723001407 |
| _version_ | 1797895576370544640 |
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| author | Satoru Matsuda Ajinkya Revandkar Taronish D. Dubash Arvind Ravi Ben S. Wittner Maoxuan Lin Robert Morris Risa Burr Hongshan Guo Karsen Seeger Annamaria Szabolcs Dante Che Linda Nieman Gad A. Getz David T. Ting Michael S. Lawrence Justin Gainor Daniel A. Haber Shyamala Maheswaran |
| author_facet | Satoru Matsuda Ajinkya Revandkar Taronish D. Dubash Arvind Ravi Ben S. Wittner Maoxuan Lin Robert Morris Risa Burr Hongshan Guo Karsen Seeger Annamaria Szabolcs Dante Che Linda Nieman Gad A. Getz David T. Ting Michael S. Lawrence Justin Gainor Daniel A. Haber Shyamala Maheswaran |
| author_sort | Satoru Matsuda |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-10T07:28:03Z |
| format | Article |
| id | doaj.art-d7cf1d03230041eaa0fc9ddd6ef3a6cf |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-10T07:28:03Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-d7cf1d03230041eaa0fc9ddd6ef3a6cf2023-02-24T04:30:38ZengElsevierCell Reports2211-12472023-03-01423112129TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent stateSatoru Matsuda0Ajinkya Revandkar1Taronish D. Dubash2Arvind Ravi3Ben S. Wittner4Maoxuan Lin5Robert Morris6Risa Burr7Hongshan Guo8Karsen Seeger9Annamaria Szabolcs10Dante Che11Linda Nieman12Gad A. Getz13David T. Ting14Michael S. Lawrence15Justin Gainor16Daniel A. Haber17Shyamala Maheswaran18Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USABroad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA 02139, USA; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USACenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Corresponding authorCenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Howard Hughes Medical Institute, Bethesda, MD 20815, USA; Corresponding authorCenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723001407CP: CancerCP: Immunology |
| spellingShingle | Satoru Matsuda Ajinkya Revandkar Taronish D. Dubash Arvind Ravi Ben S. Wittner Maoxuan Lin Robert Morris Risa Burr Hongshan Guo Karsen Seeger Annamaria Szabolcs Dante Che Linda Nieman Gad A. Getz David T. Ting Michael S. Lawrence Justin Gainor Daniel A. Haber Shyamala Maheswaran TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state Cell Reports CP: Cancer CP: Immunology |
| 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 | CP: Cancer CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723001407 |
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