The role of extracellular vesicles and PD-L1 in glioblastoma-mediated immunosuppressive monocyte induction

Benjamin T. Himes, Timothy E. Peterson, Tristan de Mooij, Luz M.Cumba Garcia, Mi Yeon Jung, Sarah Uhm, David Yan, Jasmine Tyson, Helen J. Jin-Lee, Daniel Parney, Yasmina Abukhadra, Michael P. Gustafson, Allan B. Dietz, Aaron J. Johnson, Haidong Dong, Rachel L. Maus, Svetomir Markovic, Fabrice Lucien, Ian F Parney

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)967-978
Number of pages12
JournalNeuro-oncology
Volume22
Issue number7
DOIs
StatePublished - Jul 7 2020

Keywords

  • extracellular vesicles
  • glioblastoma
  • immunosuppression

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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    Himes, B. T., Peterson, T. E., de Mooij, T., Garcia, L. M. C., Jung, M. Y., Uhm, S., Yan, D., Tyson, J., Jin-Lee, H. J., Parney, D., Abukhadra, Y., Gustafson, M. P., Dietz, A. B., Johnson, A. J., Dong, H., Maus, R. L., Markovic, S., Lucien, F., & Parney, I. F. (2020). The role of extracellular vesicles and PD-L1 in glioblastoma-mediated immunosuppressive monocyte induction. Neuro-oncology, 22(7), 967-978. https://doi.org/10.1093/neuonc/noaa029