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 Liu, Ruifeng 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 () and Wei Guo ()
Additional contact information
Gang Chen: School of Arts & Sciences, University of Pennsylvania
Alexander C. Huang: Perelman School of Medicine, University of Pennsylvania
Wei Zhang: School of Arts & Sciences, University of Pennsylvania
Gao Zhang: The Wistar Institute
Min Wu: School of Arts & Sciences, University of Pennsylvania
Wei Xu: University of Pennsylvania
Zili Yu: School and Hospital of Stomatology, Wuhan University
Jiegang Yang: School of Arts & Sciences, University of Pennsylvania
Beike Wang: School of Arts & Sciences, University of Pennsylvania
Honghong Sun: Perelman School of Medicine, University of Pennsylvania
Houfu Xia: School and Hospital of Stomatology, Wuhan University
Qiwen Man: School and Hospital of Stomatology, Wuhan University
Wenqun Zhong: School of Arts & Sciences, University of Pennsylvania
Leonardo F. Antelo: University of Pennsylvania
Bin Wu: School of Arts & Sciences, University of Pennsylvania
Xuepeng Xiong: School and Hospital of Stomatology, Wuhan University
Xiaoming Liu: Perelman School of Medicine, University of Pennsylvania
Lei Guan: School of Arts & Sciences, University of Pennsylvania
Ting Li: Perelman School of Medicine, University of Pennsylvania
Shujing Liu: Perelman School of Medicine, University of Pennsylvania
Ruifeng Yang: Perelman School of Medicine, University of Pennsylvania
Youtao Lu: School of Arts & Sciences, University of Pennsylvania
Liyun Dong: Perelman School of Medicine, University of Pennsylvania
Suzanne McGettigan: Perelman School of Medicine, University of Pennsylvania
Rajasekharan Somasundaram: The Wistar Institute
Ravi Radhakrishnan: School of Engineering, University of Pennsylvania
Gordon Mills: The University of Texas MD Anderson Cancer Center
Yiling Lu: The University of Texas MD Anderson Cancer Center
Junhyong Kim: School of Arts & Sciences, University of Pennsylvania
Youhai H. Chen: Perelman School of Medicine, University of Pennsylvania
Haidong Dong: College of Medicine, Mayo Clinic
Yifang Zhao: School and Hospital of Stomatology, Wuhan University
Giorgos C. Karakousis: Perelman School of Medicine, University of Pennsylvania
Tara C. Mitchell: Perelman School of Medicine, University of Pennsylvania
Lynn M. Schuchter: Perelman School of Medicine, University of Pennsylvania
Meenhard Herlyn: The Wistar Institute
E. John Wherry: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Xiaowei Xu: Perelman School of Medicine, University of Pennsylvania
Wei Guo: School of Arts & Sciences, University of Pennsylvania

Nature, 2018, vol. 560, issue 7718, 382-386

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0392-8

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