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

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

Research output: Contribution to journalArticlepeer-review

7 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 1 2020

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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