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The role of extracellular vesicles and PD-L1 in glioblastoma-mediated immunosuppressive monocyte induction.

细胞外囊泡和 PD-L1 在胶质母细胞瘤介导的免疫抑制单核细胞诱导中的作用。

  • 影响因子:6.99
  • DOI:10.1093/neuonc/noaa029
  • 作者列表:"Himes BT","Peterson TE","de Mooij T","Garcia MLMC","Jung MY","Uhm S","Yan D","Tyson J","Li HJL","Parney D","Abukhadra M","Gustafson MP","Dietz AB","Johnson AJ","Dong H","Maus RL","Markovic S","Lucien F","Parney IF
  • 发表时间:2020-02-21
Abstract

BACKGROUND:Immunosuppression in glioblastoma (GBM) is an obstacle to effective immunotherapy. GBM-derived immunosuppressive monocytes are central to this. Programmed death ligand-1 (PD-L1) is an immune checkpoint molecule, expressed by GBM cells and GBM extracellular vesicles (EVs). We sought to determine the role for EV-associated PD-L1 in the formation of Immunosuppressive monocytes. METHODS:Monocytes collected from healthy donors were conditioned with GBM-derived EVs to induce the formation of immunosuppressive monocytes, which were quantified via flow cytometry. Donor-matched T cells were subsequently co-cultured with EV-conditioned monocytes in order to assess effects on T cell proliferation. PD-L1 constitutitive overexpression or shRNA-mediated knockdown was used to determined the role of altered PD-L1 expression. RESULTS:GBM EVs interact with both T cells and monocytes but do not directly inhibit T cell activation. However, GBM EVs induce immunosuppressive monocytes including myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs). MDSCs and NCMs inhibit T cell proliferation in vitro and are found within GBM in situ. EV PD-L1 expression induces NCMs but not MDSCs, and does not affect EV-conditioned monocytes' T cell inhibition. CONCLUSION:These findings indicate GBM EV-mediated immunosuppression occurs through induction of immunosuppressive monocytes rather than direct T cell inhibition and that, while PD-L1 expression is important for the induction of specific immunosuppressive monocyte populations, immunosuppressive signaling mechanisms through EVs are complex and not limited to PD-L1.

摘要

背景: 胶质母细胞瘤 (GBM) 的免疫抑制是有效免疫治疗的障碍。GBM 来源的免疫抑制单核细胞对此至关重要。程序性死亡 ligand-1 (PD-L1) 是一种免疫检查点分子,由 GBM 细胞和 GBM 细胞外囊泡 (EVs) 表达。我们试图确定 EV 相关 PD-L1 在免疫抑制单核细胞形成中的作用。 方法: 收集健康供者的单核细胞,用 GBM 来源的 EVs 条件诱导免疫抑制单核细胞的形成,通过流式细胞仪进行定量。供体匹配的 T 细胞随后与 EV 条件单核细胞共培养,以评估对 T 细胞增殖的影响。PD-L1 组成型过表达或 shRNA 介导的敲除被用来确定改变 PD-L1 表达的作用。 结果: GBM EVs 与 T 细胞和单核细胞均相互作用,但不直接抑制 T 细胞活化。然而,GBM EVs 诱导免疫抑制单核细胞,包括髓源性抑制细胞 (MDSCs) 和非经典单核细胞 (NCMs)。MDSCs 和 NCMs 在体外抑制 T 细胞增殖,原位发现在 GBM 内。EV PD-L1 表达诱导 NCMs 而不是 MDSCs,并且不影响 EV 条件单核细胞的 T 细胞抑制。 结论: 这些发现表明 GBM EV 介导的免疫抑制是通过诱导免疫抑制单核细胞而不是直接 T 细胞抑制发生的,而 PD-L1 表达对诱导特异性免疫抑制单核细胞群体很重要。通过 EVs 的免疫抑制信号机制是复杂的,不限于 PD-L1。

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