Journal
ONCOGENE
Volume 37, Issue 36, Pages 4941-4954Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-018-0314-0
Keywords
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Funding
- National Institutes of Health [R01CA137098, R01CA193913, R01CA196896]
- Melanoma Research Foundation Establish Investigator Award, Hong Kong
- National Natural Science Foundation of China [81428025, 81630106, 31771619, 81673977]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine) grant
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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.
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