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Oncogene. 2018 Sep;37(36):4941-4954. doi: 10.1038/s41388-018-0314-0. Epub 2018 May 22.

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

Author information

1
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA.
2
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 210028, Nanjing, Jiangsu, China.
3
Affiliated Changzhou No. 2 People's Hospital, Nanjing Medical University, Changzhou, Jiangsu, China.
4
Department of Dermatology, Beijing Chaoyang Hospital, Capital Medical University, 100020, Beijing, China.
5
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 300193, Tianjin, China.
6
Arthritis Center/Section of Rheumatology, Boston University School of Medicine, 02118, Boston, MA, USA.
7
Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham School of Medicine, 35233, Birmingham, AL, USA.
8
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China.
9
Hunan key Laboratory of Skin Cancer and Psoriasis and Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Rd, 410008, Changsha, Hunan, China.
10
Ludwig Institute for Cancer Research, University of Oxford, Headington, Oxford, OX3 7DQ, UK.
11
Dermatology Department, Shanghai East Hospital, Tongji University, 200120, Shanghai, China. xnhrb@aliyun.com.
12
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA. rutaocui@bu.edu.
13
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 210028, Nanjing, Jiangsu, China. pcao79@yahoo.com.
14
Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, 211166, Nanjing, China. pcao79@yahoo.com.

Abstract

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.

PMID:
29786078
DOI:
10.1038/s41388-018-0314-0
[Indexed for MEDLINE]

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