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

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.