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

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Satoru Matsuda1, Ajinkya Revandkar1, Taronish D Dubash1

  • 1Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Cell Reports
|February 23, 2023
PubMed

Insights

Transforming growth factor-beta (TGF-β) induces deep senescence in hypoxic tumors, creating a 14-gene senescence-associated secretory phenotype (SASP). This SASP suppresses immune infiltration, potentially causing resistance to immune checkpoint inhibitors (ICIs).

Area of Science:

  • Cancer Biology
  • Immunology
  • Cellular Senescence

Background:

  • Transforming growth factor-beta (TGF-β) is known to induce senescence in embryonic tissues.
  • The role of TGF-β in inducing senescence within the hypoxic tumor microenvironment (TME) of cancers remains unclear.
  • The impact of the senescence-associated secretory phenotype (SASP) on TME remodeling and immune checkpoint inhibitor (ICI) response is not well understood.

Purpose of the Study:

  • To investigate whether TGF-β induces senescence in cancer cells within a hypoxic TME.
  • To determine how the resulting SASP influences the TME and affects responses to ICIs.

Main Methods:

  • Comparison of TGF-β-induced senescence under hypoxic versus normoxic conditions.
  • Analysis of deep senescence markers, including E2F suppression, multinucleation, and proliferation.
  • Characterization of a distinct 14-gene SASP.
  • Assessment of TGF-β signaling suppression in a mouse lung cancer model.
  • Evaluation of immune infiltration and SASP in human lung cancer tissues and ICI clinical trial data.

Main Results:

  • TGF-β induces a deeper senescent state under hypoxia compared to normoxia, characterized by suppressed E2F, multinucleation, and reduced proliferation.
  • A distinct 14-gene SASP is identified in deep senescence.
  • In a mouse lung cancer model, suppressing TGF-β abrogated senescent cells, the 14-gene SASP, and immune infiltration.
  • Human lung cancers with high 14-gene SASP exhibited immunosuppressive immune infiltration.
  • In an ICI clinical trial, elevated 14-gene SASP correlated with increased senescence, TGF-β/hypoxia signaling, and poorer progression-free survival.

Conclusions:

  • Hypoxia-induced TGF-β signaling drives a deep senescent state in cancer, characterized by a specific SASP.
  • This TME-induced senescence promotes an immunosuppressive phenotype, contributing to resistance against ICIs.
  • Targeting TGF-β signaling or the SASP may offer strategies to overcome ICI resistance in lung cancer.
Keywords:
CP: CancerCP: ImmunologyE2FsSASPTGF-βhypoxiaimmune checkpoint inhibitorslung cancersenescencetumor microenvironment

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