Glucocorticoids Unleash Immune-dependent Melanoma Control through Inhibition of the GARP/TGFβ Axis
Year: 2025
Type: article
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 TGFβ 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 TGFβ signaling. Furthermore, patients with melanoma with high GC receptor expression or signaling showed improved prognosis and lower TGFβ signaling in tumor-infiltrating CTLs. Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGFβ 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 TGFβ 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. See related commentary by Roest et al., p. 198.
Source: Cancer Discovery
Authors: Charles H. Earnshaw, Poppy Dunn, Shih-Chieh Chiang, Agrin Moeini, Maria A. Koufaki, Eduardo Bonavita, Massimo Russo, Laetitia Nebot-Bral, Kimberley Hockenhull, Erin Richardson, Anna Pidoux, Charlotte R. Bell, Alexander Baker, Richard Reeves, Robert Sellers, Sudhakar Sahoo, Victoria Fife, Matthew G. Roberts, Theophile Bigirumurame, Caroline Dive, Julia Newton-Bishop, Jérémie Nsengimana, Christopher E. M. Griffiths, Santiago Zelenay
Institutions: Manchester Academic Health Science Centre, University of Manchester, Salford Royal Hospital, Cancer Research UK Manchester Institute, NIHR Manchester Biomedical Research Centre, Northern Care Alliance NHS Foundation Trust, CRUK Lung Cancer Centre of Excellence, Newcastle University, University of Leeds, NIHR Newcastle Biomedical Research Centre, King's College London, King's College Hospital
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4415164517