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

Journal article

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.

Authors: Zhu, B; Tang, L; Chen, S; Yin, C; Peng, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Oncogene
• Volume: 37
• Pages: 4941–4954
• Publication date: 2018-05-22
• Acceptance date: 2018-04-20
• DOI: 10.1038/s41388-018-0314-0
• EISSN: 1476-5594
• ISSN: 0950-9232
• Keywords: cancer immunotherapy; NRF2; melanoma; PD-L1