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Sci Adv. 2018 Mar 7;4(3):eaar2766. doi: 10.1126/sciadv.aar2766. eCollection 2018 Mar.

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

Author information

1
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
3
College of Applied Medical Sciences, Taibah University, Madinah Munawwarah, Saudi Arabia.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
5
School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA.
6
Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
7
Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA.
8
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
9
Department of Neurosurgery, University of California, San Diego, La Jolla, CA 92121, USA.
10
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
11
Comprehensive Cancer Center, University of Birmingham, Birmingham, AL 35294, USA.
12
Departments of Neurology and Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, MA 02114, USA.

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 cm3. These results suggest that PD-L1 on EVs may be another mechanism for glioblastoma to suppress antitumor immunity and support the potential of EVs as biomarkers in tumor patients.

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