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：

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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。