title: Systemic T Cells Immunosuppression of Glioma Stem Cell-Derived Exosomes Is Mediated by Monocytic Myeloid-Derived Suppressor Cells.
abstract: A major contributing factor to glioma development and progression is its ability to evade the immune system. Nano-meter sized vesicles, exosomes, secreted by glioma-stem cells (GSC) can act as mediators of intercellular communication to promote tumor immune escape. Here, we investigated the immunomodulatory properties of GCS-derived exosomes on different peripheral immune cell populations. Healthy donor peripheral blood mononuclear cells (PBMCs) stimulated with anti-CD3, anti-CD28 and IL-2, were treated with GSC-derived exosomes. Phenotypic characterization, cell proliferation, Th1/Th2 cytokine secretion and intracellular cytokine production were analysed by distinguishing among effector T cells, regulatory T cells and monocytes. In unfractionated PBMCs, GSC-derived exosomes inhibited T cell activation (CD25 and CD69 expression), proliferation and Th1 cytokine production, and did not affect cell viability or regulatory T-cell suppression ability. Furthermore, exosomes were able to enhance proliferation of purified CD4+ T cells. In PBMCs culture, glioma-derived exosomes directly promoted IL-10 and arginase-1 production and downregulation of HLA-DR by unstimulated CD14+ monocytic cells, that displayed an immunophenotype resembling that of monocytic myeloid-derived suppressor cells (Mo-MDSCs). Importantly, the removal of CD14+ monocytic cell fraction from PBMCs restored T-cell proliferation. The same results were observed with exosomes purified from plasma of glioblastoma patients. Our results indicate that glioma-derived exosomes suppress T-cell immune response by acting on monocyte maturation rather than on direct interaction with T cells. Selective targeting of Mo-MDSC to treat glioma should be considered with regard to how immune cells allow the acquirement of effector functions and therefore counteracting tumor progression.
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Domenis
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cesselli
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Toffoletto
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Bourkoula
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Caponnetto
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Manini
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors.forename: Antonio Paolo
authors.initials: AP
authors.lastname: Beltrami
authors.affiliation: Department of Neurosurgery, University Hospital of Udine, Udine, Italy.
authors.forename: Tamara
authors.initials: T
authors.lastname: Ius
authors.affiliation: Department of Neurosurgery, University Hospital of Udine, Udine, Italy.
authors.forename: Miran
authors.initials: M
authors.lastname: Skrap
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Di Loreto
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors.forename: Giorgia
authors.identifier: http://orcid.org/0000-0002-2826-0459
authors.initials: G
authors.lastname: Gri
mesh_terms: D001932:Brain Neoplasms / Q000097:blood / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D055354:Exosomes / Q000276:immunology*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000097:blood / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation; D009000:Monocytes / Q000276:immunology*; D014411:Neoplastic Stem Cells / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*