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Oncoimmunology. 2018 Jan 16;7(4):e1412909. doi: 10.1080/2162402X.2017.1412909. eCollection 2018.

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

Author information

1
Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2
Institute of Biology, Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang Province, China.
3
Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Neuroimmunology Unit, Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
5
Center for Theoretical and Applied Neuro-Oncology, University of California, San Diego, CA, USA.
6
Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7
Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
9
Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
10
Laboratory for Cognitive and Molecular Morphometry, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
11
Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
12
Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
13
Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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.

KEYWORDS:

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

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