Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response

Gang Chen, Alexander C. Huang, Wei Zhang, Gao Zhang, Min Wu, Wei Xu, Zili Yu, Jiegang Yang, Beike Wang, Honghong Sun, Houfu Xia, Qiwen Man, Wenqun Zhong, Leonardo F. Antelo, Bin Wu, Xuepeng Xiong, Xiaoming Liu, Lei Guan, Ting Li, Shujing LiuRuifeng Yang, Youtao Lu, Liyun Dong, Suzanne McGettigan, Rajasekharan Somasundaram, Ravi Radhakrishnan, Gordon Mills, Yiling Lu, Junhyong Kim, Youhai H. Chen, Haidong Dong, Yifang Zhao, Giorgos C. Karakousis, Tara C. Mitchell, Lynn M. Schuchter, Meenhard Herlyn, E. John Wherry, Xiaowei Xu, Wei Guo

    Research output: Contribution to journalArticle

    274 Scopus citations

    Abstract

    Tumour cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response1,2. Anti-PD-1 antibodies have shown remarkable promise in treating tumours, including metastatic melanoma2–4. However, the patient response rate is low4,5. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amount of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumour growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 positively correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumour cells to T cell reinvigoration, stratifies clinical responders from non-responders. Our study unveils a mechanism by which tumour cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy.

    Original languageEnglish (US)
    Pages (from-to)382-386
    Number of pages5
    JournalNature
    Volume560
    Issue number7718
    DOIs
    StatePublished - Aug 16 2018

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    Cite this

    Chen, G., Huang, A. C., Zhang, W., Zhang, G., Wu, M., Xu, W., Yu, Z., Yang, J., Wang, B., Sun, H., Xia, H., Man, Q., Zhong, W., Antelo, L. F., Wu, B., Xiong, X., Liu, X., Guan, L., Li, T., ... Guo, W. (2018). Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature, 560(7718), 382-386. https://doi.org/10.1038/s41586-018-0392-8