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Published on: February 21, 2018
CSF1R Ligands Expressed by Murine Gliomas Promote M-MDSCs to Suppress CD8+ T Cells in a NOS-Dependent Manner
Gregory P Takacs1, Julia S Garcia1, Caitlyn A Hodges1
1Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Abstract:
Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2+/CX3CR1+ M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma-secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in the M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that is driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.
Insights
Myeloid-derived suppressor cells (MDSCs) drive glioblastoma immune evasion. Glioma factors like M-CSF and IL-34 promote MDSC differentiation, while adenosine and iNOS pathways mediate T cell suppression.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Biology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis.
- The GBM tumor microenvironment (TME) is immunosuppressive, hindering effective anti-tumor immunity.
- Myeloid-derived suppressor cells (MDSCs) are key immune suppressors in GBM, contributing to immune evasion.
Purpose of the Study:
- To investigate the differentiation mechanisms of monocytic MDSCs (M-MDSCs) expressing CCR2 and CX3CR1 in GBM.
- To elucidate the pathways involved in M-MDSC-mediated T cell suppression within the GBM TME.
- To explore the role of M-MDSCs in human GBM using spatial transcriptomics.
Main Methods:
- Murine glioma models were used to study M-MDSC differentiation and function.
- Glioma-derived factors were analyzed for their role in M-MDSC induction.
- Spatial RNA sequencing of human GBM tissues was employed to identify M-MDSC pathways.
Main Results:
- Bone marrow-derived CCR2+/CX3CR1+ cells acquired an immunosuppressive phenotype upon culture with glioma factors.
- CSF1R ligands (M-CSF and IL-34) secreted by glioma cells were identified as critical drivers of M-MDSC differentiation.
- Adenosine and iNOS pathways were implicated in the T cell suppressive function of M-MDSCs.
- Human GBM data revealed diverse M-MDSC-mediated suppressive pathways linked to microenvironmental niches.
Conclusions:
- Glioma-secreted factors orchestrate M-MDSC differentiation and function, contributing to immune suppression in GBM.
- Understanding these mechanisms offers potential therapeutic targets to overcome GBM immune evasion.
- This study provides a deeper insight into M-MDSC involvement in glioblastoma pathogenesis.
