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The Circadian Clock Component RORA Increases Immunosurveillance in Melanoma by Inhibiting PD-L1 Expression
Dandan Liu1,2, Benliang Wei3, Long Liang2
1Department of Dermatology, Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Clinical Research Center for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha, China.
Abstract:
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 (RORA) 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 PD-L1 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.
Insights
Retinoic acid receptor-related orphan receptor-alpha (RORA) suppresses PD-L1, enhancing anti-tumor immunity in melanoma. RORA expression predicts immunotherapy response, offering a new therapeutic target.
Area of Science:
- Cancer Biology
- Immunology
- Chronobiology
Background:
- Circadian clock disruption is common in cancer, promoting tumor growth and immune evasion.
- Clock gene disruption in melanoma is linked to immune escape.
- Retinoic acid receptor-related orphan receptor-alpha (RORA) expression is reduced in melanoma patients.
Purpose of the Study:
- To investigate the role of RORA in melanoma and its impact on anti-tumor immunity and immunotherapy response.
- To elucidate the molecular mechanism by which RORA regulates PD-L1 expression and T-cell infiltration.
- To evaluate RORA as a potential predictive biomarker and therapeutic target in melanoma.
Main Methods:
- Analysis of RORA expression in melanoma patients and correlation with prognosis and immune cell infiltration.
- Investigating the effect of RORA overexpression/activation on cytotoxic T-cell responses.
- Identifying RORA's interaction with CD274 promoter, HDAC3, and DDX3X to regulate PD-L1.
- Evaluating the synergistic effect of RORA agonist and anti-CTLA4 antibody in vivo.
- Developing a predictive score based on HDAC3, DDX3X, and RORA expression.
Main Results:
- RORA expression is downregulated in melanoma and correlates with better immunotherapy prognosis and increased T-cell infiltration.
- RORA suppresses PD-L1 expression by forming an inhibitory complex with HDAC3 on the CD274 promoter.
- DDX3X competes with HDAC3 for RORA binding, leading to increased PD-L1 expression.
- Combined RORA agonist and anti-CTLA4 therapy showed synergistic anti-tumor effects.
- A combined score of HDAC3, DDX3X, and RORA expression predicts immunotherapy response.
Conclusions:
- RORA acts as a tumor suppressor by inhibiting PD-L1 expression and promoting T-cell-mediated anti-tumor immunity.
- RORA is a potential predictive biomarker for immunotherapy response in melanoma.
- Targeting RORA or modulating its complex with HDAC3/DDX3X may improve melanoma immunotherapy outcomes.
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