Glucocorticoids Unleash Immune-dependent Melanoma Control through Inhibition of the GARP/TGF β Axis

Abstract 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, we found that, counterintuitively, glucocorticoids (GCs) elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumor control. Genetic ablation of the GC receptor in different cellular compartments revealed that GCs acted not on immune cells but directly on tumor cells to downregulate the expression of glycoprotein A repetitions predominant (GARP). This inhibited TGF β signaling and unleashed CTL killing. In agreement, GCs stimulated tumor control in multiple cancer models but only if the tumors also responded to pharmacologic inhibition of TGF β signaling. Furthermore, patients with melanoma with high GC receptor expression or signaling showed improved prognosis and lower TGF β signaling in tumor-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. Significance: This study uncovers a surprising role for GCs in triggering CD8+ T cell–dependent tumor control through downregulation of GARP and thus TGF β signaling. Analysis of samples from patients with melanoma suggested that GARP expression may serve as both a biomarker of poor antitumor immunity and a therapeutic target to improve the response to immunotherapy.