Biology subjects

Earnshaw, C. H.

Publications and source records attributed to Earnshaw, C. H..

2 recordsLinked to original sources

bioRxiv2025

Glucocorticoids unleash immune-dependent melanoma control through inhibition of the GARP/TGF-β axis

Half of advanced melanoma patients fail to benefit from immune checkpoint blockade and novel treatments are urgently required. Testing topical medications used in other skin diseases for anti-cancer activity in an immunotherapy-resistant murine melanoma model, we counterintuitively found that glucocorticoids elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumor control. Genetic ablation of the glucocorticoid receptor in different cellular compartments revealed glucocorticoids acted not on immune cells but directly on tumor cells to downregulate expression of GARP (glycoprotein A repetitions predominant). This inhibited TGF-{beta} signaling and unleashed CTL killing. In agreement, glucocorticoids stimulated tumor control in multiple cancer models, but only if the tumors also responded to pharmacological inhibition of TGF-{beta} signaling. Furthermore, melanoma patients with high glucocorticoid receptor expression or signaling showed improved prognosis and lower TGF-{beta} signaling in tumor-infiltrating CTLs. Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGF-{beta} axis emerges as a glucocorticoid-sensitive cancer cell-intrinsic immune evasive mechanism. SignificanceScreening widely used topical treatments in a melanoma model, this study uncovers a surprising role for glucocorticoids in triggering CD8+ T cell-dependent tumor control through downregulation of GARP and thus TGF-{beta} signaling. Melanoma patient sample analysis supported these findings suggesting GARP/TGF-{beta} activity functions as a tumor cell-intrinsic immune evasive mechanism, and GARP expression may serve as both a biomarker of poor antitumor immunity and a therapeutic target to improve the response to immunotherapy.

cancer biology↗

bioRxiv2018

Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

PTEN is a tumor suppressor that is often inactivated in cancer and possesses both lipid and protein phosphatase activities. We report the metabolic regulator PDHK1 (pyruvate dehydrogenase kinase1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The predominant mechanism of PDHK1 regulation and dependency is the PTEN protein phosphatase dephosphorylates NF{kappa};B activating protein (NKAP) and limits NF{kappa}B activation to suppress expression of PDHK1, a NF{kappa}B target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to drive aerobic glycolysis and induce PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, which is a biomarker of decreased patient survival, establishing clinical relevance. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.\n\nSIGNIFICANCEThe tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. PTEN antagonizes PI3K/AKT signaling via its lipid phosphatase activity. The modest success of PI3K/AKT inhibition in PTEN-deficient cancer patients provides rationale for identifying other vulnerabilities in PTEN-deficient cancers to improve clinical outcomes. We show that PTEN-deficient cells are uniquely sensitive to PDHK1 inhibition. PTEN and PDHK1 co-suppression reduced colony formation and induced cell death in vitro and tumor regression in vivo. PDHK1 levels were high in PTEN-deficient patient tumors and associated with inferior patient survival, establishing clinical relevance. Our study identifies a PTEN-regulated signaling pathway linking the PTEN protein phosphatase to the metabolic regulator PDHK1 and provides a mechanistic basis for PDHK1 targeting in PTEN-deficient cancers.

cancer biology↗