The role of extracellular vesicles and PD-L1 in glioblastoma-mediated immunosuppressive monocyte induction. Issue 7 (21st February 2020)

• Record Type: Journal Article
• Authors: Himes, Benjamin T; Peterson, Timothy E; de Mooij, Tristan; Garcia, Luz M Cumba; Jung, Mi-Yeon; Uhm, Sarah; Yan, David; Tyson, Jasmine; Jin-Lee, Helen J; Parney, Daniel; Abukhadra, Yasmina; Gustafson, Michael P; Dietz, Allan B; Johnson, Aaron J; Dong, Haidong; Maus, Rachel L; Markovic, Svetomir; Lucien, Fabrice; Parney, Ian F
• Is Part Of: Neuro-oncology. Volume 22:Issue 7(2020)
• Page Start: 967
• Page End: 978
• Publication Date: 2020-02-21
• Subjects: extracellular vesicles -- glioblastoma -- immunosuppression; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noaa029
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: Immunosuppression in glioblastoma (GBM) is an obstacle to effective immunotherapy. GBM-derived immunosuppressive monocytes are central to this. Programmed cell death ligand 1 (PD-L1) is an immune checkpoint molecule, expressed by GBM cells and GBM extracellular vesicles (EVs). We sought to determine the role of EV-associated PD-L1 in the formation of immunosuppressive monocytes. Methods: Monocytes collected from healthy donors were conditioned with GBM-derived EVs to induce the formation of immunosuppressive monocytes, which were quantified via flow cytometry. Donor-matched T cells were subsequently co-cultured with EV-conditioned monocytes in order to assess effects on T-cell proliferation. PD-L1 constitutive overexpression or short hairpin RNA–mediated knockdown was used to determined the role of altered PD-L1 expression. Results: GBM EVs interact with both T cells and monocytes but do not directly inhibit T-cell activation. However, GBM EVs induce immunosuppressive monocytes, including myeloid-derived suppressor cells (MDSCs) and nonclassical monocytes (NCMs). MDSCs and NCMs inhibit T-cell proliferation in vitro and are found within GBM in situ. EV PD-L1 expression induces NCMs but not MDSCs, and does not affect EV-conditioned monocytes T-cell inhibition. Conclusion: These findings indicate that GBM EV-mediated immunosuppression occurs through induction of immunosuppressive monocytes rather than direct T-cell inhibition and that, while PD-L1 expression is important for the induction of specific immunosuppressive monocyte populations, immunosuppressive signaling mechanisms through EVs are complex and not limited to PD-L1.