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. Here, 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.

中文翻译：

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昼夜节律时钟成分 RORA 通过抑制 PD-L1 表达来增强黑色素瘤的免疫监视


生物钟扰动经常发生在癌症中，并通过调节恶性生长和塑造免疫微环境来促进肿瘤进展。新的证据表明，黑色素瘤中的时钟基因被破坏，并与免疫逃逸有关。在此，我们发现黑色素瘤患者中视黄酸受体相关孤儿受体-α（RORA）的表达下调，并且RORA表达较高的患者在免疫治疗后预后较好。此外，RORA 与 T 细胞浸润和募集显着正相关。 RORA 的过度表达或激活刺激细胞毒性 T 细胞介导的抗肿瘤反应。 RORA 与 CD274 启动子结合并与 HDAC3 形成抑制复合物以抑制 PD-L1 表达。相比之下，DEAD-box解旋酶家族成员DDX3X与HDAC3竞争与RORA的结合，并且DDX3X过度表达促进RORA从抑制复合物中释放，从而增加PD-L1表达以产生抑制性免疫环境。 RORA激动剂与抗CTLA4抗体的组合可协同增强体内T细胞抗肿瘤免疫力。基于 HDAC3、DDX3X 和 RORA 组合表达的评分与黑色素瘤患者的免疫治疗反应相关。总之，这项研究阐明了时钟成分调节的抗肿瘤免疫机制，这将有助于为免疫疗法的使用提供信息，并改善接受联合治疗的黑色素瘤患者的预后。