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68th Annual Meeting of the German Society of Neurosurgery (DGNC)
7th Joint Meeting with the British Neurosurgical Society (SBNS)

German Society of Neurosurgery (DGNC)

14 - 17 May 2017, Magdeburg

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Glioblastoma-derived extracellular vesicles dynamically carry PD-L1 and specifically inhibit CD4+ and CD8+ T-cell activation and proliferation

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  • Franz Ricklefs - Universitätsklinikum Hamburg-Eppendorf, Klinik für Neurochirurgie, Brigham and Women's Hospital, Harvard Medical School, Depratment of Neurosurgery, Hamburg, Deutschland
  • Maria Speranza - Brigham and Women's Hospital, Harvard Medical School, Department of Neurosurgery, Boston, United States
  • Sean Lawler - Brigham and Women's Hospital, Harvard Medical School, Department of Neurosurgery, Boston, United States
  • Manfred Westphal - Universitätsklinikum Hamburg-Eppendorf, Klinik für Neurochirurgie, Hamburg, Deutschland
  • Ennio Antonio Chiocca - Brigham and Women's Hospital, Harvard Medical School, Department of Neurosurgery, Boston, United States

Deutsche Gesellschaft für Neurochirurgie. Society of British Neurological Surgeons. 68. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 7. Joint Meeting mit der Society of British Neurological Surgeons (SBNS). Magdeburg, 14.-17.05.2017. Düsseldorf: German Medical Science GMS Publishing House; 2017. DocMi.28.03

doi: 10.3205/17dgnc560, urn:nbn:de:0183-17dgnc5604

Published: June 9, 2017

© 2017 Ricklefs et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

Text

Objective: Extracellular Vesicles (EVs) shed by tumor cells have recently been demonstrated to act a major conduits in cell-cell communication. However, knowledge of the effect of EVs on infiltrating lymphocytes within the tumor microenvironment is still rudimental. In this study we investigated the potential role of EVs in immune escape in heterogeneous glioblastoma.

Methods: Peripheral blood mononuclear cells (PBMCs) (n=8) were stimulated by IL-2 or anti-CD3±anti-CD28 treatment. Magnetic cell sorting was used to isolate CD3+ cells. Activation levels of CD3+CD4+ and CD3+CD8+ were monitored by flow cytometry of the T cell activation markers CD69 and CD25. Concurrent eFlour staining was used to measure proliferation. EVs derived from six different glioblastoma stem-like cell lines (GSCs) from either the mesenchymal (M) or proneural (P) subtype were used in this study. PDL1 expression was validated by immunoblotting and single EV analysis (SEA) and measured after IFNy stimulation. EV binding was visualized by PALM-tomato positive EVs.

Results: EVs were able to bind to the outer surface of CD3+ cells. In whole PBMCs EV treatment led to a significant reduction of CD3+CD8+ and CD3+CD4+ T-cell activation as well as proliferation and IL-4 expression, especially in the M subtype. These effects were also observed in CD3+ sorted cells, indicating a direct effect of EVs on T cells. In contrast, increased IL-10 expression in PBMCs after EV treatment was lost on CD3+ sorted T-cells indicating that EVs also influence other CD3- cells in the PBMC population. PDL1 expression on EVs was inducible by IFNy stimulation of GSCs.

Conclusion: Our findings demonstrate the immunosuppressive potential of GSC-derived EVs. Furthermore we identified PDL1 expression in EVs as a dynamic regulator that may be partially responsible for these effects.