掷骰子
生物
免疫系统
癌症研究
肿瘤微环境
促炎细胞因子
巨噬细胞极化
巨噬细胞
免疫学
炎症
细胞培养
小干扰RNA
转染
遗传学
生物化学
体外
作者
Yuqi Liu,Min Luo,Yu Shi,Ying Guo,Hua Zhang,Kai‐Di Yang,Tianran Li,Liuqing Yang,Tingting Liu,Bo Huang,Qing Liu,Zhicheng He,Xiaoning Zhang,Wenying Wang,Shuai Wang,Hui Zeng,Qin Niu,Xia Zhang,You‐Hong Cui,Zhiren Zhang,Xiu‐Wu Bian,Yi‐Fang Ping
出处
期刊:Oncogene
[Springer Nature]
日期:2022-06-28
卷期号:41 (30): 3791-3803
标识
DOI:10.1038/s41388-022-02393-9
摘要
Glioblastoma is a lethal primary brain tumor with abundant immune-suppressive glioblastoma-associated macrophage (GAM) infiltration. Skewing immune suppressive GAMs towards an immune-activating phenotype represents a promising immunotherapeutic strategy against glioblastoma. Herein, we reported that genetic deletion of miRNA-processing enzyme Dicer in macrophages inhibited the growth of GL261 murine glioblastoma xenografts and prolonged survival of tumor-bearing mice. Single cell RNA sequencing (scRNA-seq) of the tumor-infiltrating immune cells revealed that Dicer deletion in macrophages reduced the proportion of cell-cycling GAM cluster and reprogramed the remaining GAMs towards a proinflammatory activation state (enhanced phagocytotic and IFN-producing signature). Dicer-deficient GAMs showed reduced level of cyclin-dependent kinases (CDK1 and CDK2) and increased expression of CDK inhibitor p27 Kip1, thus manifesting impaired proliferation. Dicer knockout enhanced phagocytotic activity of GAMs to eliminate GL261 tumor cells. Increased proinflammatory GAM clusters in macrophage Dicer-deficient mice actively interacted with tumor-infiltrating T cells and NK cells through TNF paracrine signaling to create a pro-inflammatory immune microenvironment for tumor cell elimination. Our work identifies the role of Dicer deletion in macrophages in generating an immune-activating microenvironment, which could be further developed as a potential immunotherapeutic strategy against glioblastoma.
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