Altered Metabolism in Glioblastoma: Myeloid-Derived Suppressor Cell (MDSC) Fitness and Tumor-Infiltrating Lymphocyte (TIL) Dysfunction

Abstract

The metabolism of glioblastoma (GBM), the most aggressive and lethal primary brain tumor, is flexible and adaptable to different adverse conditions, such as nutrient deprivation. Beyond glycolysis, altered lipid metabolism is implicated in GBM progression. Indeed, metabolic subtypes were recently identified based on divergent glucose and lipid metabolism. GBM is also characterized by an immunosuppressive microenvironment in which myeloid-derived suppressor cells (MDSCs) are a powerful ally of tumor cells. Increasing evidence supports the interconnection between GBM and MDSC metabolic pathways. GBM cells exert a crucial contribution to MDSC recruitment and maturation within the tumor microenvironment, where the needs of tumor-infiltrating lymphocytes (TILs) with antitumor function are completely neglected. In this review, we will discuss the unique or alternative source of energy exploited by GBM and MDSCs, exploring how deprivation of specific nutrients and accumulation of toxic byproducts can induce T-cell dysfunction. Understanding the metabolic programs of these cell components and how they impact fitness or dysfunction will be useful to improve treatment modalities, including immunotherapeutic strategies.

The immunosuppressive microenvironment and immunotherapy in human glioblastoma

“…Loss of CCR2 expression resulted in a reduced outflow of MDSCs in the bone marrow, thereby reducing GBM infiltration of these cells. Other studies demonstrated that CCL2 mediates the migration and accumulation of MDSCs at tumor sites, which not only inhibits the killing function of natural killer (NK) cells and the anti-tumor immune effect of T cells but also promotes the development of Tregs and limits the maturation of DCs, thereby inhibiting innate and adaptive immunity ( 37 – 39 ). MDSCs can use metabolic pathways to mature from bone marrow precursors owing to their high glycolysis flux, and this process indirectly leads to effector T-cell inhibition through the consumption of carbon sources ( 40 ).…”

Emerging roles of ferroptosis in glioma

“…In brain tumor patients, immunological dysfunction is a major obstacle to immunotherapy ( 155 ). Some infiltrating immune cells in the tumor microenvironment such as Treg cells ( 162 ), myeloid-derived suppressor cells ( 163 ), etc. are also engaged in immunotherapy resistance.…”

Kynureninase Promotes Immunosuppression and Predicts Survival in Glioma Patients: In Silico Data Analyses of the Chinese Glioma Genome Atlas (CGGA) and of the Cancer Genome Atlas (TCGA)

“…GBM’s poor prognosis has been attributed mainly to its high biological complexity, which is insufficiently understood [ 6 ]. The multiple genetic alterations in GBM confer several biological advantages, such as treatment resistance, high proliferation and metabolic adaptations that allow modulation of the tumor microenvironment (TME) [ 7 ]. In this context, mutations in the active site of isocitrate dehydrogenase 1 (IDH1), a catalytic enzyme that produces alpha-ketoglutarate (α-KG) by oxidative decarboxylation of isocitrate [ 8 ], have been related to a better prognosis in glioma patients.…”