Glioma-derived extracellular vesicles selectively suppress immune responses

Hellwinkel, Justin E.; Redzic, Jasmina S.; Harland, Tessa A.; Gunaydin, Dicle; Anchordoquy, Thomas J.; Graner, Michael W.

doi:10.1093/neuonc/nov170

Cited by 91 publications

(96 citation statements)

References 46 publications

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“…In accordance with Hellwinkel el al. [23], we reported that GSC-derived exosomes downregulate the activation of PBMCs in terms of proliferation and cytokines production. We demonstrated that the proliferation of CD4+ T within PBMCs treated with GSC-derived exosomes was inhibited, whereas there were no significant effects on CD8+ T cells, supporting the results obtained in [34], in which glioma-derived exosomes failed to alter the activation and INF-γ production by CD8+ T cells.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study revealed that exosomes from murine-derived glioblastoma GL26 cell line promote tumor growth by inhibiting the number and function of cytotoxic CD8 + T cells in vivo [22]. Moreover, GBM-derived vesicles affect cytokine output and migratory capabilities of mitogen-stimulated healthy peripheral blood mononuclear cells (PBMCs) [23] and skew the differentiation of peripheral blood-derived monocytes to alternatively activated M2 tumor-supportive macrophages [24]. Although not all the aspects related to the exosome-induced tumor progression and tolerance have been understood, exosomes could represent potential glioma biomarkers and specific targets to improve tumor immunotherapy [25].…”

Section: Introductionmentioning

confidence: 99%

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Systemic T Cells Immunosuppression of Glioma Stem Cell-Derived Exosomes Is Mediated by Monocytic Myeloid-Derived Suppressor Cells

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systemic T Cells Immunosuppression of Glioma Stem Cell-Derived Exosomes Is Mediated by Monocytic Myeloid-Derived Suppressor Cells

et al. 2017

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“…EVs are able to modulate angiogenesis, an important factor in cancer progression (26)(27)(28)(29). EVs have also been shown to modulate the anti-tumoral response by affecting the immune response, T-cell activation and natural killer cell induction (30)(31)(32)(33). EVs can also contribute to drug resistance via various mechanisms, including the sequestration of drugs (34,35) and the transfer of proteins or RNA (36)(37)(38)(39) (40)(41)(42)(43)(44)(45).…”

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confidence: 99%

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Samuel

Mulcahy

Furlong

et al. 2017

Phil. Trans. R. Soc. B

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Ovarian cancer has a poor overall survival that is partly caused by resistance to drugs such as cisplatin. Resistance can be acquired as a result of changes to the tumour or due to altered interactions within the tumour microenvironment. Extracellular vesicles (EVs), small lipid-bound vesicles that are loaded with macromolecular cargo and released by cells, are emerging as mediators of communication in the tumour microenvironment. We previously showed that EVs mediate the bystander effect, a phenomenon in which stressed cells can communicate with neighbouring naive cells leading to various effects including DNA damage; however, the role of EVs released following cisplatin treatment has not been tested. Here we show that treatment of cells with cisplatin led to the release of EVs that could induce invasion and increased resistance when taken up by bystander cells. This coincided with changes in p38 and JNK signalling, suggesting that these pathways may be involved in mediating the effects. We also show that EV uptake inhibitors could prevent this EV-mediated adaptive response and thus sensitize cells in vitro to the effects of cisplatin. Our results suggest that preventing pro-tumourigenic EV cross-talk during chemotherapy is a potential therapeutic target for improving outcome in ovarian cancer patients. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

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“…UPN933 cells were cultured from an anaplastic oligodendroglioma (WHO grade III) obtained on a study approved by the Colorado Combined Institutional Review Board (COMIRB), #95-100. Cells were cultured under “stem-cell conditions” as described [15, 97] and in Supplementary Materials. STR analysis and verification were performed in Nov 2014 by the UCCC PPSR.…”

Section: Methodsmentioning

confidence: 99%

Proteomic analyses of brain tumor cell lines amidst the unfolded protein response

et al. 2016

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Brain tumors such as high grade gliomas are among the deadliest forms of human cancers. The tumor environment is subject to a number of cellular stressors such as hypoxia and glucose deprivation. The persistence of the stressors activates the unfolded proteins response (UPR) and results in global alterations in transcriptional and translational activity of the cell. Although the UPR is known to effect tumorigenesis in some epithelial cancers, relatively little is known about the role of the UPR in brain tumors. Here, we evaluated the changes at the molecular level under homeostatic and stress conditions in two glioma cell lines of differing tumor grade. Using mass spectrometry analysis, we identified proteins unique to each condition (unstressed/stressed) and within each cell line (U87MG and UPN933). Comparing the two, we find differences between both the conditions and cell lines indicating a unique profile for each. Finally, we used our proteomic data to identify the predominant pathways within these cells under unstressed and stressed conditions. Numerous predominant pathways are the same in both cell lines, but there are differences in biological and molecular classifications of the identified proteins, including signaling mechanisms, following UPR induction; we see that relatively minimal proteomic alterations can lead to signaling changes that ultimately promote cell survival.

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Glioma-derived extracellular vesicles selectively suppress immune responses

Cited by 91 publications

References 46 publications

Systemic T Cells Immunosuppression of Glioma Stem Cell-Derived Exosomes Is Mediated by Monocytic Myeloid-Derived Suppressor Cells

Systemic T Cells Immunosuppression of Glioma Stem Cell-Derived Exosomes Is Mediated by Monocytic Myeloid-Derived Suppressor Cells

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Proteomic analyses of brain tumor cell lines amidst the unfolded protein response

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