Article highlights & insights
Half of patients with advanced melanoma fail to benefit from immune checkpoint blockade, and novel treatments are urgently required. Testing topical medications for anticancer activity in an immunotherapy-resistant murine melanoma model, the authors found that, counterintuitively, glucocorticoids (GCs) elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumour control. Genetic ablation of the GC receptor in different cellular compartments revealed that GCs acted not on immune cells but directly on tumour cells to downregulate the expression of glycoprotein A repetitions predominant (GARP).
This inhibited TGF β signalling and unleashed CTL killing. In agreement, GCs stimulated tumour control in multiple cancer models but only if the tumours also responded to pharmacologic inhibition of TGF β signalling. Furthermore, patients with melanoma with high GC receptor expression or signalling showed improved prognosis and lower TGF β signaling in tumour-infiltrating CTLs.
Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGF β axis emerges as a GC-sensitive cancer cell–intrinsic immune-evasive mechanism.
This study uncovers a surprising role for GCs in triggering CD8+ T cell–dependent tumour control through downregulation of GARP and thus TGF β signalling. Analysis of samples from patients with melanoma suggested that GARP expression may serve as both a biomarker of poor antitumour immunity and a therapeutic target to improve the response to immunotherapy.
Half of patients with advanced melanoma fail to benefit from immune checkpoint blockade, and novel treatments are urgently required. Testing topical medications for anticancer activity in an immunotherapy-resistant murine melanoma model, the authors found that, counterintuitively, glucocorticoids (GCs) elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumour control. Genetic ablation of the GC receptor in different cellular compartments revealed that GCs acted not on immune cells but directly on tumour cells to downregulate the expression of glycoprotein A repetitions predominant (GARP).
This inhibited TGF β signalling and unleashed CTL killing. In agreement, GCs stimulated tumour control in multiple cancer models but only if the tumours also responded to pharmacologic inhibition of TGF β signalling. Furthermore, patients with melanoma with high GC receptor expression or signalling showed improved prognosis and lower TGF β signaling in tumour-infiltrating CTLs.
Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGF β axis emerges as a GC-sensitive cancer cell–intrinsic immune-evasive mechanism.
This study uncovers a surprising role for GCs in triggering CD8+ T cell–dependent tumour control through downregulation of GARP and thus TGF β signalling. Analysis of samples from patients with melanoma suggested that GARP expression may serve as both a biomarker of poor antitumour immunity and a therapeutic target to improve the response to immunotherapy.