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.
复制标题
神经胶质瘤干细胞衍生外泌体的全身性T细胞免疫抑制是由单核细胞衍生的抑制细胞介导的。
DOI：
10.1371/journal.pone.0169932
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Gri G
中科院分区：
文献类型：
--
作者：
Domenis R;Cesselli D;Toffoletto B;Bourkoula E;Caponnetto F;Manini I;Beltrami AP;Ius T;Skrap M;Di Loreto C;Gri G
胶质瘤发展和进展的一个主要因素是其逃避免疫系统的能力。胶质瘤干细胞（GSC）分泌的纳米囊泡（exosomes）可作为细胞间通讯的介质，促进肿瘤免疫逃逸。在这里，我们研究了GCS衍生的外泌体对不同外周免疫细胞群体的免疫调节特性。用抗-CD 3、抗-CD 28和IL-2刺激的健康供体外周血单核细胞（PBMC）用GSC衍生的外泌体处理。通过区分效应T细胞、调节T细胞和单核细胞，分析表型表征、细胞增殖、Th 1/Th 2细胞因子分泌和细胞内细胞因子产生。在未分级的PBMC中，GSC衍生的外泌体抑制T细胞活化（CD 25和CD 69表达）、增殖和Th 1细胞因子产生，并且不影响细胞活力或调节性T细胞抑制能力。此外，外泌体能够增强纯化的CD 4 + T细胞的增殖。在PBMC培养中，胶质瘤来源的外泌体直接促进IL-10和HLA-DR-1的产生，并通过未刺激的CD 14+单核细胞下调HLA-DR，其显示类似于单核细胞骨髓来源的抑制细胞（Mo-MDSC）的免疫表型。重要的是，从PBMC中去除CD 14+单核细胞部分恢复了T细胞增殖。用从胶质母细胞瘤患者的血浆纯化的外来体观察到相同的结果。我们的研究结果表明，胶质瘤源性外泌体通过作用于单核细胞成熟而不是与T细胞直接相互作用来抑制T细胞免疫应答。选择性靶向Mo-MDSC治疗胶质瘤应考虑免疫细胞如何允许获得效应功能，从而抵消肿瘤进展。
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.