Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy

• Published in: Oncogene Vol. 37; no. 36; pp. 4941 - 4954
• Main Authors: Zhu, Bo, Tang, Liming, Chen, Shuyang, Yin, Chengqian, Peng, Shiguang, Li, Xin, Liu, Tongzheng, Liu, Wei, Han, Changpeng, Stawski, Lukasz, Xu, Zhi-Xiang, Zhou, Guangbiao, Chen, Xiang, Gao, Xiumei, Goding, Colin R., Xu, Nan, Cui, Rutao, Cao, Peng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2018; Nature Publishing Group
• Subjects: 13/1; 13/105; 13/109; 13/21; 13/31; 13/44; 13/51; 13/89; 13/95; 38/1; 631/67/1813/1634; 631/80; 82/51; Animals; Antibodies; Antineoplastic agents; Antitumor activity; Apoptosis; B7-H1 Antigen - metabolism; Biochemistry; Biopharmaceuticals; Cancer treatment; CD4 antigen; CD8 antigen; Cell Biology; Cell death; Cell Line, Tumor; Female; Gene expression; HEK293 Cells; Human Genetics; Humans; Immune checkpoint; Immune response; Internal Medicine; Lymphocytes T; Medical schools; Medicine; Medicine & Public Health; Melanoma; Melanoma - metabolism; Metastases; Mice; Mice, Inbred C57BL; Oncology; PD-1 protein; PD-L1 protein; Radiation (Physics); Retirement benefits; Signal Transduction - physiology; Skin; T cells; Transcription (Genetics); Transcription, Genetic - physiology; Transcriptional Activation - physiology; Transcriptional coactivators; Tumors; Ultraviolet radiation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0314-0

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.