Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance
Abstract
1. Introduction
2. Circulating Neutrophils in Glioma Progression and Treatment Resistance
3. TANs in Glioma Progression
4. TANs and Treatment Resistance in Glioma
4.1. Chemotherapy and Anti-VEGF Therapy Resistance
4.2. RT Resistance
4.3. Immunotherapy Resistance
5. MDSCs in Glioma Progression
6. MDSCs and Treatment Resistance in Glioma
6.1. MDSC-Mediated Immunosuppression and Therapy Resistance in Glioma
6.2. MDSCs and RT Resistance
7. Conclusions and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
Arg1 | Arginase-1 |
GBM | Glioblastoma |
GM-CSF | Granulocyte macrophage colony stimulating factor |
GME | Glioma microenvironment |
GSCs | Glioma stem cells |
IFN | Interferon |
IL | Interleukin |
iNOS | Inducible nitric oxide synthase |
MDSCs | Myeloid-derived suppressor cells |
NFκB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
NK cells | Natural killer cells |
NLR | Neutrophil-to-lymphocyte ratio |
PD-L1 | Programmed death-ligand 1 |
PMN-MDSCs | Granulocytic polymorphonuclear MDSCs |
ROS | Reactive oxygen species |
RT | Radiation therapy |
STAT-3 | Signal transducer and activator of transcription 3 |
TANs | Tumor-associated neutrophils |
TGF-β | Transforming growth factor beta |
TMZ | Temozolomide |
VEGF | Vascular endothelial growth factor |
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Mechanism/Inference | Test Systems | Specific Cells Used | References |
---|---|---|---|
Glioma-derived factors affect circulating neutrophils and influence their infiltration into the tumors | In vivo human | Blood neutrophils and tumor sections | [36] |
Neutrophils enhance proliferation of GSCs and promote glioma progression and resistance against anti-vascular endothelial growth factor (VEGF) therapy via upregulation of S100A4 | Mixed (in vitro and in vivo in both human and mouse) | Tumor tissue microarray, GSCs and mouse xenografts | [18] |
Neutrophil degranulation is associated with elevated levels of circulating Arg1, which promotes tumor growth and immunosuppression | In vitro and in vivo human | Blood neutrophils and tumor sections | [37] |
Increased neutrophil activation levels indicate early signs of tumor progression and provide prognostic value in glioblastoma (GBM) | In vivo human | Blood neutrophils and serum | [38] |
Immunosuppression within the tumor is driven by the overexpression and production of G-CSF and S100A4 | Mixed (in vitro and in vivo in both human and mouse) | Glioma cells, GSCs and blood samples | [18,41] |
IL-6 and IL-8 partially mediated by glioma cells have a protective effect on blood neutrophils | In vitro human | Blood neutrophils and glioma cells | [46] |
Depletion of neutrophils via monoclonal antibody against Ly6G prolongs the survival of mice with developing gliomas | Mixed (in vitro and in vivo in mouse, and in vitro human) | Transgenic mice and patients’ blood | [47] |
TANs are associated with tumor aggressiveness in mutant-IDH1 glioma | Mixed (in vivo mouse and human) | Transgenic mice, patients tumor tissue and blood cells/RNA | [21] |
Primary glioma cells sustaining NOS2 activity promote proliferation, migration, and neurosphere generation and represent a prognostic factor for glioma malignancy and recurrence | Human in vitro | Glioma cell lines and primary culture | [48] |
Radiation-induced infiltrating Ly6G+ neutrophils support the conversion of GBM tumor cells to GSCs via the regulation of nitrosative stress and dedifferentiation (NOS2-NO-ID4) signaling in newly diagnosed/recurrent GBM patients, and this is negatively associated with survival and radiation therapy outcomes | Mixed (in vitro and in vivo in both human and mouse) | Human glioma cell lines, tumor single cells, and glioma mouse models | [49] |
In a CIBERSORT comparative analysis of immune cell fractions, mesenchymal subtypes of GBM have higher levels of TANs than other subtypes | Human in vitro and in vivo | GSCs and GBM tumor tissue | [50] |
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Khan, S.; Mittal, S.; McGee, K.; Alfaro-Munoz, K.D.; Majd, N.; Balasubramaniyan, V.; de Groot, J.F. Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance. Int. J. Mol. Sci. 2020, 21, 1954. https://doi.org/10.3390/ijms21061954
Khan S, Mittal S, McGee K, Alfaro-Munoz KD, Majd N, Balasubramaniyan V, de Groot JF. Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance. International Journal of Molecular Sciences. 2020; 21(6):1954. https://doi.org/10.3390/ijms21061954
Chicago/Turabian StyleKhan, Sabbir, Sandeep Mittal, Kain McGee, Kristin D. Alfaro-Munoz, Nazanin Majd, Veerakumar Balasubramaniyan, and John F. de Groot. 2020. "Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance" International Journal of Molecular Sciences 21, no. 6: 1954. https://doi.org/10.3390/ijms21061954
APA StyleKhan, S., Mittal, S., McGee, K., Alfaro-Munoz, K. D., Majd, N., Balasubramaniyan, V., & de Groot, J. F. (2020). Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance. International Journal of Molecular Sciences, 21(6), 1954. https://doi.org/10.3390/ijms21061954