expression is downregulated in melanoma patients, with higher levels associated with better immunotherapy prognosis.
Patients with elevated RORA expression show improved outcomes following immunotherapy.
RORA is positively correlated with T-cell infiltration in the tumor microenvironment.
Activating RORA enhances the effectiveness of cytotoxic T-cells against tumors.
RORA inhibits expression by binding to its promoter and interacting with HDAC3.
DDX3X competes with HDAC3 for RORA binding, promoting PD-L1 expression and creating an immune-suppressive environment.
A scoring system based on HDAC3, DDX3X, and RORA expression correlates with immunotherapy responses in melanoma.
Simplified
Circadian clock perturbation frequently occurs in cancer and facilitates tumor progression by regulating malignant growth and shaping the immune microenvironment. Emerging evidence has indicated that clock genes are disrupted in melanoma and linked to immune escape. Herein, we found that the expression of retinoic acid receptor-related orphan receptor-α () is downregulated in melanoma patients and that patients with higher RORA expression have a better prognosis after immunotherapy. Additionally, RORA was significantly positively correlated with T-cell infiltration and recruitment. Overexpression or activation of RORA stimulated cytotoxic T-cell-mediated antitumor responses. RORA bound to the CD274 promoter and formed an inhibitory complex with HDAC3 to suppress expression. In contrast, the DEAD-box helicase family member DDX3X competed with HDAC3 for binding to RORA, and DDX3X overexpression promoted RORA release from the suppressive complex and thereby increased PD-L1 expression to generate an inhibitory immune environment. The combination of a RORA agonist with an anti-CTLA4 antibody synergistically increased T-cell antitumor immunity in vivo. A score based on the combined expression of HDAC3, DDX3X, and RORA correlated with immunotherapy response in melanoma patients. Together, this study elucidates a mechanism of clock component-regulated antitumor immunity, which will help inform the use of immunotherapy and lead to improved outcomes for melanoma patients receiving combined therapeutic treatments. Significance: RORA forms a corepressor complex to inhibit PD-L1 expression and activate antitumor T-cell responses, indicating that RORA is a potential target and predictive biomarker to improve immunotherapy response in melanoma patients.
Key numbers
177 patients
Prognosis Correlation
Patients analyzed for expression and immunotherapy outcomes.
25 mg/kg
Tumor Growth Reduction
Dosage administered for nobiletin treatment in vivo.
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