间质干细胞作为胶质瘤外泌体免疫抑制信号的倍增器，通过 miR-21/SP1/DNMT1 正反馈环增强 MDSC 的免疫抑制活性。

Mesenchymal stem cells, as glioma exosomal immunosuppressive signal multipliers, enhance MDSCs immunosuppressive activity through the miR-21/SP1/DNMT1 positive feedback loop.

机构信息

Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road, Jinan, Shandong, 250012, China.

Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China.

出版信息

J Nanobiotechnology. 2023 Jul 22;21(1):233. doi: 10.1186/s12951-023-01997-x.

DOI:10.1186/s12951-023-01997-x

PMID:37481646

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10362641/

Abstract

BACKGROUND

The immunosuppressive microenvironment in glioma induces immunotherapy resistance and is associated with poor prognosis. Glioma-associated mesenchymal stem cells (GA-MSCs) play an important role in the formation of the immunosuppressive microenvironment, but the mechanism is still not clear.

RESULTS

We found that GA-MSCs promoted the expression of CD73, an ectonucleotidase that drives immunosuppressive microenvironment maintenance by generating adenosine, on myeloid-derived suppressor cells (MDSCs) through immunosuppressive exosomal miR-21 signaling. This process was similar to the immunosuppressive signaling mediated by glioma exosomal miR-21 but more intense. Further study showed that the miR-21/SP1/DNMT1 positive feedback loop in MSCs triggered by glioma exosomal CD44 upregulated MSC exosomal miR-21 expression, amplifying the glioma exosomal immunosuppressive signal. Modified dendritic cell-derived exosomes (Dex) carrying miR-21 inhibitors could target GA-MSCs and reduce CD73 expression on MDSCs, synergizing with anti-PD-1 monoclonal antibody (mAb).

CONCLUSIONS

Overall, this work reveals the critical role of MSCs in the glioma microenvironment as signal multipliers to enhance immunosuppressive signaling of glioma exosomes, and disrupting the positive feedback loop in MSCs with modified Dex could improve PD-1 blockade therapy.

摘要

背景

胶质瘤中的免疫抑制微环境诱导免疫治疗耐药，并与预后不良相关。胶质瘤相关间充质干细胞（GA-MSCs）在免疫抑制微环境的形成中起重要作用，但具体机制尚不清楚。

结果

我们发现 GA-MSCs 通过免疫抑制性外泌体 miR-21 信号促进髓系来源抑制细胞（MDSCs）上 CD73 的表达，CD73 是一种通过产生腺苷来驱动免疫抑制微环境维持的外核苷酸酶。这一过程类似于由胶质瘤外泌体 miR-21 介导的免疫抑制信号，但更为强烈。进一步研究表明，胶质瘤外泌体 CD44 触发的 MSC 中 miR-21/SP1/DNMT1 正反馈环上调 MSC 外泌体 miR-21 的表达，放大了胶质瘤外泌体的免疫抑制信号。携带 miR-21 抑制剂的修饰树突状细胞衍生的外泌体（Dex）可以靶向 GA-MSCs，并降低 MDSCs 上的 CD73 表达，与抗 PD-1 单克隆抗体（mAb）协同作用。