A CSF-1R-blocking antibody/IL-10 fusion protein increases anti-tumor immunity by effectuating tumor-resident CD8+ T cells
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ABSTRACT:
PROVIDER: PRJNA892115 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21973448_1.fastq.gz | Fastqsanger.gz | |||
| SRR21973448_2.fastq.gz | Fastqsanger.gz | |||
| SRR21973449_1.fastq.gz | Fastqsanger.gz | |||
| SRR21973449_2.fastq.gz | Fastqsanger.gz | |||
| SRR21973450_1.fastq.gz | Fastqsanger.gz |
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2024-08-12 | PXD041689 | Pride
Project description:Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor in adults, can be divided into several molecular subtypes including proneural GBM. Most clinical strategies aimed at directly targeting glioma cells in these tumors have failed. A promising alternative is to target stromal cells in the brain microenvironment, such as tumor-associated microglia and macrophages (TAMs). Macrophages are dependent upon colony stimulating factor (CSF)-1 for differentiation and survival; therefore, we used an inhibitor of its receptor, CSF-1R, to target macrophages in a mouse proneural GBM model. CSF-1R inhibition dramatically increased survival in mice and regressed established GBMs. Tumor cell apoptosis was significantly increased, and proliferation and tumor grade markedly decreased. Surprisingly, TAMs were not depleted in tumors treated with the CSF-1R inhibitor. Instead, analysis of gene expression in TAMs isolated from treated tumors revealed a decrease in alternatively activated/ M2 macrophage markers, consistent with impaired tumor-promoting functions. These gene signatures were also associated with better survival specifically in the proneural subtype of patient gliomas. Collectively, these results establish macrophages as valid therapeutic targets in proneural gliomas, and highlight the clinical potential for CSF-1R inhibitors in GBM.
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Project description:CSF-1R is recruited on EGR1 motifs in monocytes where it colocalizes with EGR1. To address if EGR1 required for CSF-1R recruitment on chromatin, THP-1 monocytic cell line has been deleted for EGR1 by CRISPR-Cas9 approach. 3 clones were generated by single cell cloning and CSF-1R localization on chromatin was compared to two unmodified THP-1 clones by ChIP-sequencing. Since the read number was strongly decreased in the EGR1-deleted clones, the three clones were pooled for the comparison with wild-type clones. ChIPseq of CSF-1R (Nter Antibody) in monocytes of two CMML patients (CMML2130 and CMML2609)
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