Glioblastoma stem cell-derived exosomes induce M2 macrophages and PD-L1 expression on human monocytes

Konrad Gabrusiewicz, Xu Li, Jun Wei, Yuuri Hashimoto, Anantha L. Marisetty, Martina Ott, Fei Wang, David Hawke, John Yu, Luke M. Healy, Anwar Hossain, Johnny C. Akers, Sourindra N. Maiti, Shinji Yamashita, Yuzaburo Shimizu, Kenneth Dunner, M. Anna Zal, Jared K. Burks, Joy Gumin, Felix NwajeiAras Rezavanian, Shouhao Zhou, Ganesh Rao, Raymond Sawaya, Gregory N. Fuller, Jason T. Huse, Jack P. Antel, Shulin Li, Laurence Cooper, Erik P. Sulman, Clark Chen, Changiz Geula, Raghu Kalluri, Tomasz Zal, Amy B. Heimberger

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Exosomes can mediate a dynamic method of communication between malignancies, including those sequestered in the central nervous system and the immune system. We sought to determine whether exosomes from glioblastoma (GBM)-derived stem cells (GSCs) can induce immunosuppression. We report that GSC-derived exosomes (GDEs) have a predilection for monocytes, the precursor to macrophages. The GDEs traverse the monocyte cytoplasm, cause a reorganization of the actin cytoskeleton, and skew monocytes toward the immune suppresive M2 phenotype, including programmed death-ligand 1 (PD-L1) expression. Mass spectrometry analysis demonstrated that the GDEs contain a variety of components, including members of the signal transducer and activator of transcription 3 (STAT3) pathway that functionally mediate this immune suppressive switch. Western blot analysis revealed that upregulation of PD-L1 in GSC exosome-treated monocytes and GBM-patient-infiltrating CD14+ cells predominantly correlates with increased phosphorylation of STAT3, and in some cases, with phosphorylated p70S6 kinase and Erk1/2. Cumulatively, these data indicate that GDEs are secreted GBM-released factors that are potent modulators of the GBM-associated immunosuppressive microenvironment.

Original languageEnglish (US)
Article numbere1412909
JournalOncoImmunology
Volume7
Issue number4
DOIs
StatePublished - Apr 3 2018

Bibliographical note

Funding Information:
These studies were supported by the Anthony Bullock III Foundation, Cynthia and George Mitchell Foundation, the Dr. Marnie Rose Foundation, the Ben and Catherine Ivy Foundation, the Provost Retention Fund, and the National Institutes of Health CA1208113, P50 CA127001, and P50 CA093459. Electron microscopy was performed by the High Resolution Electron Microscopy Facility, and the flow cytometric analysis was performed by the Flow Cytometry and Cellular Imaging Facility, which are partly supported by the NIH through The University of Texas MD Anderson Cancer Center Support Grant P30 CA016672. Mass spectrometry analysis was performed by the Proteomics and Metabolomics Facility supported by the Cancer Prevention Research Institute of Texas RP130397 and NIH 1S10OD012304-01. Fluorescence microscopy was performed in the Advanced Microscopy Core Facility, which is partly supported by the NIH through the 1S10RR029552 grant.

Keywords

  • PD-L1
  • STAT3
  • cancer stem cells
  • exosome
  • glioblastoma
  • immune cells

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