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

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, transcri...

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Bibliografische gegevens
Hoofdauteurs: Zhu, B, Tang, L, Chen, S, Yin, C, Peng, S, Li, X, Liu, T, Liu, W, Han, C, Stawski, L, Xu, Z, Zhou, G, Chen, X, Gao, X, Goding, C, Xu, N, Cui, R, Cao, P
Formaat: Journal article
Gepubliceerd in: Springer Nature 2018
Omschrijving
Samenvatting: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.