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.

Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain

“…To date, only 1 evidence would suggest the occurrence of an aberrant senescent program as a strategy of immune evasion in brain cancer. Indeed, Domenis et al . recently demonstrated that glioma stem cells (GSCs) express and in turn induce the secretion by monocytic myeloid‐derived suppressor cells, of many SASP factors, that can act as mediators of intercellular communication to promote systemic tumor immune escape.…”

Contribution of the Microenvironmental Niche to Glioblastoma Heterogeneity

“…It is believed that MDSCs interact with gliomas and GSCs [169]; however, the exact mechanisms of crosstalk remain undefined. Using CD133 and Sox2, Otvos and colleagues found significant amount of MDSCs located directly adjacent to GSCs [149], suggesting possible interaction between GSCs and MDSCs in the tumor microenvironment.…”

Emergence of exosomal DNA in molecular neuropathology

“…This is another challenging aspect as it is not yet clarified if analysis of exoDNA is applicable to identify genomic patterns of distinct glioma cell subpopulations that may drive tumor progression. Recent studies on the potential use of exosomes imply an important role of exoDNA in irradiation of gliomas [125], immune suppression of gliomas [126], anti-tumor immune activity [90] and hypoxia [127] showing numerous potential novel approaches in using EV in brain tumor research and diagnostics.…”