Dataset Information

Integrated single-cell transcriptomic analyses reveal that GPNMB-high macrophages promote PN-MES transition and impede T cell activation in GBM.

ABSTRACT:

Background

Glioblastoma (GBM) is the most aggressive type of primary brain tumor and is often resistant to current therapies. Tumor microenvironment-centered therapies may unleash new hope for GBM treatment. Therefore, an in-depth understanding of tumor-stroma communication is urgently needed to identify promising therapeutic targets.

Methods

We systematically analyzed GBM single-cell RNA sequencing (scRNA-seq), bulk RNA-seq and spatial scRNA-seq data from various human and mice studies to characterize the network within the microenvironment. Moreover, we applied ex vivo co-culture system, flow cytometry analysis and immunofluorescent staining to validate our findings.

Findings

Our integrative analyses revealed that highly heterogeneous GBM tumor cells can be classified into MES-like, AC-like, OPC-like and NPC-like subtypes based on molecular studying. Additionally, trajectory and regulatory network inference implied a PN to MES cell state transition regulated by specific transcriptional factor (TF) regulons. Importantly, we discovered that glycoprotein nonmetastatic B (GPNMB) derived from macrophages played a crucial role in this transition through immune cell-tumor interplay. Besides, through deep signal transduction analyses and cell co-culture studies, we further disclosed that these GPNMB-high macrophage subpopulations, originating from monocytes, could also ineffectively retain T cells from activating by dendritic cells (DCs).

Interpretation

Our study suggests that targeting this particular GPNMB-high macrophage subset may provide a new strategy to control GBM plasticity and facilitate T cell-based immunotherapy.

Funding

A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

SUBMITTER: Xiong A

PROVIDER: S-EPMC9437813 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Integrated single-cell transcriptomic analyses reveal that GPNMB-high macrophages promote PN-MES transition and impede T cell activation in GBM.

Xiong Aizhen A Zhang Jiwei J Chen Yan Y Zhang Yi Y Yang Fan F

EBioMedicine 20220830

<h4>Background</h4>Glioblastoma (GBM) is the most aggressive type of primary brain tumor and is often resistant to current therapies. Tumor microenvironment-centered therapies may unleash new hope for GBM treatment. Therefore, an in-depth understanding of tumor-stroma communication is urgently needed to identify promising therapeutic targets.<h4>Methods</h4>We systematically analyzed GBM single-cell RNA sequencing (scRNA-seq), bulk RNA-seq and spatial scRNA-seq data from various human and mice s ...[more]

PMID: 36054938

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Dataset Information

Integrated single-cell transcriptomic analyses reveal that GPNMB-high macrophages promote PN-MES transition and impede T cell activation in GBM.

Background

Methods

Findings

Interpretation

Funding

Publications

Integrated single-cell transcriptomic analyses reveal that GPNMB-high macrophages promote PN-MES transition and impede T cell activation in GBM.

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