G-CSF Secreted by Epigenetically Reprogrammed Mutant IDH1 Glioma Stem Cells Reverses the Myeloid Cells’-Mediated Immunosuppressive Tumor Microenvironment

Abstract

Mutation in isocitrate dehydrogenase (mIDH) is a gain of function mutation resulting in the production of the oncometabolite, R-2-hydroxyglutarate, that inhibits DNA and histone demethylases. The resultant hypermethylation phenotype reprograms the glioma cells’ transcriptome and elicits profound effects on glioma immunity. We report that in mouse models and human gliomas, mIDH1 in the context of ATRX and TP53 inactivation results in global expansion of the granulocytic myeloid cells’ compartment. Single-cell RNA-sequencing coupled with mass cytometry analysis revealed that these granulocytes are mainly non-immunosuppressive neutrophils and pre-neutrophils; with a small fraction of polymorphonuclear myeloid-derived suppressor cells. The mechanism of mIDH1 mediated pre-neutrophils expansion involves epigenetic reprogramming which leads to enhanced expression of the granulocyte colony-stimulating factor (G-CSF). Blocking G-CSF restored the inhibitory potential of PMN-MDSCs and enhanced tumor progression. Thus, G-CSF induces remodeling of the inhibitory PMN-MDSCs in mIDH1 glioma rendering them non-immunosuppressive; and having significant therapeutic implications.SIGNIFICANCEmIDH1 is the most common mutation in gliomas associated with improved prognosis. Gliomas harboring mIDH1, together with ATRX and TP53 inactivation, exhibit higher circulating levels of G-CSF, ensuing the recruitment and expansion of non-suppressive neutrophils, pre-neutrophils and small fraction of PMN-MDSCs to the TME leading to an immune permissive phenotype.

Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

“…Myeloid cells are the most frequent immune cell type in the glioma TME, accounting for ∼60% of all glioma infiltrating immune cells. In GBM, myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells that hamper glioma immune response ( Kamran et al, 2017 ; Alghamri et al, 2020 ). Clinically, the frequency of MDSCs is associated with an unfavorable prognosis in glioma ( Rahbar et al, 2016 ).…”

Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

“…Myeloid-derived suppressor cells (MDSC) are a type of immature myeloid cells that are known to have immunosuppressive functions via different mechanisms that ultimately inhibit T cell functions (9,11,13). These cells have been found in the blood of glioma patients and in the tumor mass, and they have also been characterized in animal models (9,15,89,90) (91). It has been observed that the quantity and activation status of MDSC inversely correlates with patient survival and that they can be a predictor of WHO tumor grade (90).…”

“…Also, and in correlation to what Luoto et al found, mIDH1 gliomas tend to have less macrophages than wt-IDH1 tumors ( 97 ). Moreover, in an animal model of mIDH1 glioma in the context of ATRX and TP53 mutations, it has been observed that the presence of this mutation reprograms the tumor cell transcriptome, which affects not only immune cell infiltration but also the bone marrow differentiation of the granulocytic lineage ( 15 ). This effect was found to be mediated by G-CSF secretion by mIDH1 glioma cells, which prompted the expansion of pre-neutrophils, while reducing the immunosuppressive phenotype of the granulocytes encountered in mIDH1 tumors’ TME ( 15 ).…”

“…However, work from our team reported that infiltrating immune myeloid cells in the mutant-IDH TME are devoid of immunosuppressive properties. This highlights that it is not only important to identify the presence of a particular immune cells population using defined molecular markers, but also to assess the functional activity of these cells, to be able to describe the characteristics of the TME ( 15 ). In addition, it has been reported that mutant-IDH glioma cells express lower PD-L1 levels due to epigenetic reprogramming, suggesting a less immunosuppressive environment.…”

“…This review aims to discuss several aspects related to the glioma immune-microenvironment and the newest strategies that could emerge as a result of the latest pre-clinical investigations. Firstly, we will present the available clinical data regarding the immune microenvironment in glioma and its particularities in terms of tumor classification and molecular features (7,(13)(14)(15), as well as the current immune-mediated strategies being tested in the pre-clinical field (16). Also, we will overview the present immune-stimulatory therapeutic modalities being tested in clinical trials (8,17).…”