Dual targeting macrophages and microglia is atherapeutic vulnerability in models of PTEN-deficient glioblastoma

被引：4

作者：

Liu, Yang

Wu, Junyan

Najem, Hinda

Lin, Yiyun ^{[1
,4
]}

Pang, Lizhi

Khan, Fatima

Zhou, Fei

Ali, Heba

Heimberger, Amy B.

Chen, Peiwen ^{[2
,3
,5
]}

机构：

[1] Northwestern Univ, Feinberg Sch Med, Dept Neurol Surg, Chicago, IL USA

[2] Cleveland Clin, Dept Canc Biol, Lerner Res Inst, Cleveland Hts, OH USA

[3] Univ Texas MD Anderson Canc Ctr Houston, Dept Immunol, Houston, TX USA

[4] Univ Texas MD Anderson Canc Ctr Houston, UTHealth Grad Sch Biomed Sci, Houston, TX USA

[5] Case Comprehens Canc Ctr, Cleveland, OH USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2024年 / 134卷 / 22期

关键词：

TUMOR-SUPPRESSOR PTEN; STEM-CELLS; GENE; EXPRESSION; MICROENVIRONMENT; IMMUNOTHERAPY; BEVACIZUMAB; LANDSCAPE; SYMBIOSIS; BRAIN;

D O I：

10.1172/JCI178628

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-kappa B-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent antitumor effects and offers a complete tumor regression in more than 60% of animals when combined with anti-PD1 therapy in PTEN-deficient GBM mouse models. Thus, our findings provide a translational triple therapeutic strategy for this lethal disease.

引用

页数：16

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