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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number112129
JournalCell Reports
Volume42
Issue number3
DOIs
Publication statusPublished - 2023 Mar 28
Externally publishedYes

Keywords

  • CP: Cancer
  • CP: Immunology
  • E2Fs
  • hypoxia
  • immune checkpoint inhibitors
  • lung cancer
  • SASP
  • senescence
  • TGF-β
  • tumor microenvironment

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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