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

Autor: Ricklefs FL; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Alayo Q; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Krenzlin H; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Mahmoud AB; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; College of Applied Medical Sciences, Taibah University, Madinah Munawwarah, Saudi Arabia., Speranza MC; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Nakashima H; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Hayes JL; School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA., Lee K; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA., Balaj L; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA., Passaro C; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Rooj AK; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Krasemann S; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Carter BS; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA., Chen CC; Department of Neurosurgery, University of California, San Diego, La Jolla, CA 92121, USA., Steed T; Department of Neurosurgery, University of California, San Diego, La Jolla, CA 92121, USA., Treiber J; Department of Neurosurgery, University of California, San Diego, La Jolla, CA 92121, USA., Rodig S; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA., Yang K; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA., Nakano I; Comprehensive Cancer Center, University of Birmingham, Birmingham, AL 35294, USA., Lee H; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA., Weissleder R; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA., Breakefield XO; Departments of Neurology and Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, MA 02114, USA., Godlewski J; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Westphal M; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Lamszus K; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Freeman GJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Bronisz A; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Lawler SE; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Chiocca EA; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2018 Mar 07; Vol. 4 (3), pp. eaar2766. Date of Electronic Publication: 2018 Mar 07 (Print Publication: 2018).
DOI: 10.1126/sciadv.aar2766
Abstrakt: 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 3 . 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.
Databáze: MEDLINE