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 melanoma2,3,4. 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.
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We thank S. Fuchs and J. Ridley (University of Pennsylvania) for their helpful comments. This work is supported by NIH grants GM111128 and GM085146 to W.G., AI105343, AI108545, AI082630, AI117950, Parker Institute for Cancer Immunotherapy to E.J.W., 2T32CA009615-26 to A.C.H., American Heart Association to G.C., CA114046, CA025874, CA010815, CA193417, CA047159, P50 CA174523 (SPORE) and the Tara Miller Foundation to M.H., L.M.S., G.C.K., T.C.M., W.G., X.Xu., the University of Pennsylvania and the Wistar Institute, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to M.H., the CAST foundation 2016QNRC001, 2015QNRC001 to Wuhan University, and the NSFC foundation 81570994 to Y.Z.
Nature thanks H. Peinado, T. Tueting and the other anonymous reviewer(s) for their contribution to the peer review of this work.