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Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles

2018; American Association for the Advancement of Science; Volume: 4; Issue: 3 Linguagem: Inglês

10.1126/sciadv.aar2766

2375-2548

Franz Ricklefs, Quazim A. Alayo, Harald Krenzlin, Ahmad Bakur Mahmoud, Maria C. Speranza, Hiroshi Nakashima, Josie Hayes, Kyungheon Lee, Leonora Balaj, Carmela Passaro, Arun K. Rooj, Susanne Krasemann, Bob S. Carter, Clark C. Chen, Tyler Steed, Jeffrey M. Treiber, Scott J. Rodig, Katherine S. Yang, Ichiro Nakano, Hakho Lee, Ralph Weissleder, Xandra O. Breakefield, Jakub Godlewski, Manfred Westphal, Katrin Lamszus, Gordon J. Freeman, Agnieszka Bronisz, Sean E. Lawler, E. Antonio Chiocca,

Immune cells in cancer

Binding of programmed death ligand-1 (PD-L1) to programmed cell death protein-1 (PD1) leads to cancer immune evasion via inhibition of T cell function. One of the defining characteristics of glioblastoma, a universally fatal brain cancer, is its profound local and systemic immunosuppression. Glioblastoma has also been shown to generate extracellular vesicles (EVs), which may play an important role in tumor progression. We thus hypothesized that glioblastoma EVs may be important mediators of immunosuppression and that PD-L1 could play a role. We show that glioblastoma EVs block T cell activation and proliferation in response to T cell receptor stimulation. PD-L1 was expressed on the surface of some, but not of all, glioblastoma-derived EVs, with the potential to directly bind to PD1. An anti-PD1 receptor blocking antibody significantly reversed the EV-mediated blockade of T cell activation but only when PD-L1 was present on EVs. When glioblastoma PD-L1 was up-regulated by IFN-γ, EVs also showed some PD-L1-dependent inhibition of T cell activation. PD-L1 expression correlated with the mesenchymal transcriptome profile and was anatomically localized in the perinecrotic and pseudopalisading niche of human glioblastoma specimens. PD-L1 DNA was present in circulating EVs from glioblastoma patients where it correlated with tumor volumes of up to 60 cm