Clinical and experimental immunology · 2026
Nebivolol prevents exhausted T cells and enhances cytotoxicity against MCF-7 breast cancer cells in a β2-adrenergic receptor-dependent manner.
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Hajiaghayi Mehri, Gholizadeh Fatemeh, Rahbari Niloufar, Emamnia Negaralsadat, Shih Steve C C, Darlington Peter J
Аннотация
INTRODUCTION: Cancers often drive T cells toward an exhausted state characterized by impaired cytotoxicity and upregulation of inhibitory receptors (PD-1, TIM-3, CD38) and transcriptional regulators (TOX, NFATc1). Repeated stimulation in vitro is used to model this process, reflecting chronic antigen exposure in the tumor microenvironment. Stress-derived catecholamines further drive dysfunction through β-adrenergic receptor (β-AR) signaling. Here, we examined the impact of nebivolol, an atypical β1-AR blocker with β2-biased agonist activity, on T-cell exhaustion and cytotoxicity against breast cancer cells.
METHODS: Human CD3+ T cells from healthy participants were activated once (early activation) or four times (repeated activation) using CD3/CD28/CD2 T cell activator. Cells were treated in vitro with nebivolol, terbutaline (β2-agonist), isoproterenol (β1/β2-agonist), and metoprolol (β1-blocker). Exhaustion markers, including PD-1, TIM-3, CD38, and TOX, were measured by flow cytometry and RT-qPCR; NFATc1 by western blot; TNF and IFN-γ by ELISA, and cytotoxicity against MCF-7 breast carcinoma cells by co-culture assays. Disruption of the β2-AR gene (ADRB2) was achieved using CRISPR/Cas9.
RESULTS: Nebivolol reduced the proportion of TIM-3+CD38+PD-1+ T cells, downregulated TOX and nuclear NFATc1, and restored ADRB2 expression under repeated activation conditions. Nebivolol enhanced TNF secretion and improved cytotoxicity against MCF-7 cells. In contrast, terbutaline and isoproterenol had no significant effect on exhaustion markers or cytotoxicity. Metoprolol did not inhibit nebivolol's activity, indicating that its effects are not β1-AR-dependent. Disruption of ADRB2 indicated that nebivolol's anti-exhaustion effects are mediated by β2-AR.
DISCUSSION: These findings show that nebivolol reinvigorates CD4+ and CD8+ T cells following repeated activation, restoring their cytotoxic function against breast cancer cells in vitro. The immunomodulatory activity of Nebivolol is independent of β1-AR and mediated through β2-AR, suggesting that biased β2-AR signaling may represent a potential strategy for modulating T cell exhaustion in the tumor microenvironment.
METHODS: Human CD3+ T cells from healthy participants were activated once (early activation) or four times (repeated activation) using CD3/CD28/CD2 T cell activator. Cells were treated in vitro with nebivolol, terbutaline (β2-agonist), isoproterenol (β1/β2-agonist), and metoprolol (β1-blocker). Exhaustion markers, including PD-1, TIM-3, CD38, and TOX, were measured by flow cytometry and RT-qPCR; NFATc1 by western blot; TNF and IFN-γ by ELISA, and cytotoxicity against MCF-7 breast carcinoma cells by co-culture assays. Disruption of the β2-AR gene (ADRB2) was achieved using CRISPR/Cas9.
RESULTS: Nebivolol reduced the proportion of TIM-3+CD38+PD-1+ T cells, downregulated TOX and nuclear NFATc1, and restored ADRB2 expression under repeated activation conditions. Nebivolol enhanced TNF secretion and improved cytotoxicity against MCF-7 cells. In contrast, terbutaline and isoproterenol had no significant effect on exhaustion markers or cytotoxicity. Metoprolol did not inhibit nebivolol's activity, indicating that its effects are not β1-AR-dependent. Disruption of ADRB2 indicated that nebivolol's anti-exhaustion effects are mediated by β2-AR.
DISCUSSION: These findings show that nebivolol reinvigorates CD4+ and CD8+ T cells following repeated activation, restoring their cytotoxic function against breast cancer cells in vitro. The immunomodulatory activity of Nebivolol is independent of β1-AR and mediated through β2-AR, suggesting that biased β2-AR signaling may represent a potential strategy for modulating T cell exhaustion in the tumor microenvironment.