Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma
Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B. Heimberger, Peiwen Chen
Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B. Heimberger, Peiwen Chen
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Research Article Oncology

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

Abstract

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-κB-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.

Authors

Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B. Heimberger, Peiwen Chen

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Figure 2

Macrophages negatively related to microglia in GBM tumors.

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Macrophages negatively related to microglia in GBM tumors. (A) High-reso...
(A) High-resolution UMAP dimensional reduction of myeloid cells, including macrophages, microglia, monocytes (Mono), dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs), from tumors from patients with GBM based on the scRNA-seq dataset (GSE182109). (B) Percentage of different types of myeloid cells in tumors of low-grade gliomas (LGG), newly diagnosed GBM (ndGBM) and recurrent GBM (rGBM) based on above scRNA-seq data. (C) Correlation between macrophages and microglia in the GBM TME based on the above scRNA-seq data. Pearson test. (D) Representative image of multiplex sequential immunofluorescence showing the distribution of P2RY12+ microglia, CD163+ macrophages, GFAP+ tumor cells, and CD31+ blood vessels in the tumor edges and tumors from IDH1-WT GBM patients. Scale bar: 500 μm. (E and F) Higher magnified view of CD163+ macrophages and P2RY12+ microglia in the tumor edges and tumors from IDH1-WT GBM patients. Scale bar: 100 μm.