Department 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.
Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, China.
Cancer Res. 2024 Jul 15;84(14):2265-2281. doi: 10.1158/0008-5472.CAN-23-3942.
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.
生物钟节律紊乱在癌症中频繁发生，通过调节恶性生长和塑造免疫微环境促进肿瘤进展。新出现的证据表明，时钟基因在黑色素瘤中被打乱，并与免疫逃逸有关。在此，我们发现视黄酸受体相关孤儿受体-α（RORA）在黑色素瘤患者中的表达下调，并且 RORA 表达较高的患者在接受免疫治疗后预后更好。此外，RORA 与 T 细胞浸润和募集呈显著正相关。过表达或激活 RORA 可刺激细胞毒性 T 细胞介导的抗肿瘤反应。RORA 与 CD274 启动子结合，并与 HDAC3 形成抑制性复合物以抑制 PD-L1 的表达。相反，DEAD 盒解旋酶家族成员 DDX3X 与 HDAC3 竞争结合 RORA，DDX3X 过表达促进 RORA 从抑制性复合物中释放，从而增加 PD-L1 的表达，从而产生抑制性免疫环境。RORA 激动剂与抗 CTLA4 抗体联合使用可在体内协同增强 T 细胞抗肿瘤免疫。基于 HDAC3、DDX3X 和 RORA 的联合表达的评分与黑色素瘤患者的免疫治疗反应相关。总之，该研究阐明了时钟元件调节抗肿瘤免疫的机制，这将有助于为接受联合治疗的黑色素瘤患者提供免疫治疗的信息，并改善他们的治疗效果。意义：RORA 形成一个核心抑制复合物以抑制 PD-L1 的表达并激活抗肿瘤 T 细胞反应，表明 RORA 是提高黑色素瘤患者免疫治疗反应的潜在靶点和预测生物标志物。
