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

TLDR

Glioblastoma induces profound local and systemic immunosuppression, and its extracellular vesicles (EVs) may contribute to tumor progression by presenting PD‑L1, which binds PD‑1 to inhibit T‑cell function. The study hypothesized that glioblastoma‑derived EVs mediate immunosuppression via PD‑L1. Glioblastoma EVs inhibit T‑cell activation, an effect mediated by surface PD‑L1—as demonstrated by reversal with anti‑PD‑1, up‑regulation by IFN‑γ, correlation with a mesenchymal transcriptome, perinecrotic localization, and detection of PD‑L1 DNA in patient EVs linked to tumor volume.

Abstract

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