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Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy.
Oncogene ( IF 6.9 ) Pub Date : 2018-Sep-01 , DOI: 10.1038/s41388-018-0314-0
Bo Zhu , Liming Tang , Shuyang Chen , Chengqian Yin , Shiguang Peng , Xin Li , Tongzheng Liu , Wei Liu , Changpeng Han , Lukasz Stawski , Zhi-Xiang Xu , Guangbiao Zhou , Xiang Chen , Xiumei Gao , Colin R. Goding , Nan Xu , Rutao Cui , Peng Cao

Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death protein-1 (PD-1) as an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcriptional suppression of PD-L1 expression as an alternative therapeutic anti-melanoma strategy has not been exploited. Here we provide biochemical evidence demonstrating that ultraviolet radiation (UVR) induction of PD-L1 in skin is directly controlled by nuclear factor E2-related transcription factor 2 (NRF2). Depletion of NRF2 significantly induces tumor infiltration by both CD8+ and CD4+ T cells to suppress melanoma progression, and combining NRF2 inhibition with anti-PD-1 treatment enhanced its anti-tumor function. Our studies identify a critical and targetable PD-L1 upstream regulator and provide an alternative strategy to inhibit the PD-1/PD-L1 signaling in melanoma treatment.

中文翻译:

靶向PD-L1的上游转录激活因子,作为黑色素瘤治疗的替代策略。

程序性细胞死亡配体1(PD-L1)与程序性细胞死亡蛋白1(PD-1)相互作用作为免疫检查点。通过使用治疗性抗体抑制PD-L1来重新激活免疫反应在许多(但不是全部)黑素瘤患者中提供了可观的临床益处。然而,尚未开发出PD-L1表达的转录抑制作为一种替代性治疗性抗黑素瘤策略。在这里,我们提供了生化证据,证明皮肤中PD-L1的紫外线(UVR)诱导直接受核因子E2相关转录因子2(NRF2)的控制。NRF2的耗竭显着诱导CD8 +和CD4 +浸润肿瘤T细胞可抑制黑色素瘤的进展,并将NRF2抑制与抗PD-1治疗相结合可增强其抗肿瘤功能。我们的研究确定了关键的和可靶向的PD-L1上游调节剂,并提供了在黑色素瘤治疗中抑制PD-1 / PD-L1信号传导的替代策略。
更新日期:2018-05-22
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