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TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state.

ABSTRACT: 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.

SUBMITTER: Matsuda S

PROVIDER: S-EPMC10187541 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state.

Matsuda Satoru S Revandkar Ajinkya A Dubash Taronish D TD Ravi Arvind A Wittner Ben S BS Lin Maoxuan M Morris Robert R Burr Risa R Guo Hongshan H Seeger Karsen K Szabolcs Annamaria A Che Dante D Nieman Linda L Getz Gad A GA Ting David T DT Lawrence Michael S MS Gainor Justin J Haber Daniel A DA Maheswaran Shyamala S

Cell reports 20230222 3

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 in ...[more]

PMID: 36821441

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TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state.

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TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state.

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