TGF-ß in the microenvironment induces a physiologically occurring immune-suppressive senescent state.
Cell Rep
; 42(3): 112129, 2023 03 28.
Article
em En
| MEDLINE
| ID: mdl-36821441
ABSTRACT
TGF-ß induces senescence in embryonic tissues. Whether TGF-ß 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-ß 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-ß 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-ß 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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta
/
Neoplasias Pulmonares
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article