音猬因子
癌症研究
髓母细胞瘤
小RNA
刺猬信号通路
小胶质细胞
下调和上调
化学
生物
免疫学
信号转导
细胞生物学
炎症
生物化学
基因
作者
Liangyi Zhu,Ying Yang,Haishuang Li,Long Xu,Huanyu You,Yantao Liu,Zongran Liu,Xiaodan Liu,Danfeng Zheng,Juntao Bie,Jiaqi Li,Chao Song,Yijun Bao,Jianyuan Luo,Qing Chang
出处
期刊:Cancer Letters
[Elsevier]
日期:2022-06-01
卷期号:535: 215630-215630
被引量:12
标识
DOI:10.1016/j.canlet.2022.215630
摘要
Medulloblastoma (MB), the most common malignant pediatric brain tumor, is composed of at least four molecular subgroups with distinct clinical characteristics. The sonic hedgehog (SHH) subgroup exhibits the most abundant tumor-associated microglia/macrophages (TAMs) infiltration. SHH-MB patients treated by anti-SHH drugs showed high drug resistance. However, the comprehensive role of TAMs in SHH-MB remains enigma. The aim of this study is to explore the mechanism of TAM activation/polarization in SHH-MB and discover a potential immunotherapeutic target to reduce drug resistance. We first analyzed expression profiles of immuno-microenvironment (IME) in four subgroups of 48 MB tumors using NanoString PanCancer IO360 panel and found TAMs were the major component of IME in SHH-MBs. We further distinguished M1/M2-like TAMs in tumors and found M2-like macrophages, rather than microglia, were enriched in SHH-MBs. In transgenic SHH-MB mice, these TAMs had close relationship with tumor progression. Polarization of the TAMs could be induced by MB-derived exosomes in vitro. We then screened SHH MB-derived exosomal miRNAs and their target genes using RNA sequencing and luciferase assay to clarify their roles in regulating TAM polarization. We found down-regulated let-7i-5p and miR-221-3p can induce M2-like polarization of TAMs via upregulating peroxisome proliferator activated receptor gamma (PPARγ). Finally, we demonstrated the PPARγ antagonist efficiently improved the antitumor activity of SMO inhibitor in vivo, which may be related to inhibition of M2-like TAMs. Our findings suggest a potential therapeutic strategy for SHH-MB by targeting tumor-supportive M2-like TAMs to enhance the therapeutic effect of SMO inhibitors.
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