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

Oncogene volume 37, pages 4941–4954 (2018)Cite this article

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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.

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Acknowledgements

We thank Drs. Wenshu Wu and Rui He for carefully reading and suggestions. This work was supported by the National Institutes of Health (RC: R01CA137098, R01CA193913 and R01CA196896), Melanoma Research Foundation Establish Investigator Award (RC), Hong Kong, Macao Young Scientists of the National Natural Science Foundation of China (Grant No.81428025 for RC) and National Natural Science Foundation of China (81630106), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine) grant (PC). National Natural Science Foundation of China (31771619) for HH. The National Natural Science Foundation of China (Grant No. 81673977 for 2016 for XM). RC is an American Cancer Society Research Scholar.

Author contributions

BZ, LT, SC, and CY performed most of the experiments with assistance from SP, XL, TL, WL, CH, LS, ZX, GZ, XC, and XG. PC, RC, and NX designed and supervised the experiments. RC, NX, and PC wrote the manuscript with assistance from CG.

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Author notes

  1. These authors contributed equally: Bo Zhu, Liming Tang, Shuyang Chen, Chengqian Yin.

Authors and Affiliations

  1. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA

    Bo Zhu, Shuyang Chen, Chengqian Yin, Shiguang Peng, Xin Li, Tongzheng Liu, Wei Liu, Changpeng Han & Rutao Cui

  2. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 210028, Nanjing, Jiangsu, China

    Liming Tang & Peng Cao

  3. Affiliated Changzhou No. 2 People’s Hospital, Nanjing Medical University, Changzhou, Jiangsu, China

    Liming Tang

  4. Department of Dermatology, Beijing Chaoyang Hospital, Capital Medical University, 100020, Beijing, China

    Shiguang Peng

  5. Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 300193, Tianjin, China

    Wei Liu & Xiumei Gao

  6. Arthritis Center/Section of Rheumatology, Boston University School of Medicine, 02118, Boston, MA, USA

    Lukasz Stawski

  7. Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham School of Medicine, 35233, Birmingham, AL, USA

    Zhi-Xiang Xu

  8. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China

    Guangbiao Zhou

  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

    Xiang Chen

  10. Ludwig Institute for Cancer Research, University of Oxford, Headington, Oxford, OX3 7DQ, UK

    Colin R. Goding

  11. Dermatology Department, Shanghai East Hospital, Tongji University, 200120, Shanghai, China

    Nan Xu

  12. Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, 211166, Nanjing, China

    Peng Cao

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  1. Bo Zhu
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Correspondence to Nan Xu, Rutao Cui or Peng Cao.

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These authors contributed equally: Bo Zhu, Liming Tang, Shuyang Chen, Chengqian Yin.

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Zhu, B., Tang, L., Chen, S. et al. Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy. Oncogene 37, 4941–4954 (2018). https://doi.org/10.1038/s41388-018-0314-0

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