Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma

Abstract

Glioblastoma, also known as glioblastoma multi-forme, is the most common and deadliest form of high-grade malignant brain tumors with limited available treatments. Within the glioblastoma tumor microenvironment (TME), tumor cells, stromal cells, and infiltrating immune cells continuously interact and exchange signals through various secreted factors including cytokines, chemokines, growth factors, and metabolites. Simultaneously, they dynamically reprogram their metabolism according to environmental energy demands such as hypoxia and neo-vascularization. Such metabolic re-programming can determine fates and functions of tumor cells as well as immune cells. Ultimately, glioma cells in the TME transform immune cells to suppress anti-tumor immune cells such as T, natural killer (NK) cells, and dendritic cells (DC), and evade immune surveillance, and even to promote angiogenesis and tumor metastasis. Glioma-associated microglia/macrophages (GAMM) and myeloid-derived suppressor cells (MDSC) are most abundantly recruited and expanded myeloid lineage cells in glioblastoma TME and mainly lead to immunosuppression. In this review, of myeloid cells we will focus on MDSC as an important driver to induce immunosuppression in glioblastoma. Here, we review current literature on immunosuppressive functions and metabolic reprogramming of MDSCs in glioblastoma and discuss their metabolic pathways as potential therapeutic targets to improve current incurable glioblastoma treatment.

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…Tables 1-3). Hence, if TAMs influence immune and adaptive signaling, reciprocally, loco-regional metabolic signals produced in tumor environments (glucose, glutamine, cystéine, lactate, IDO, adenosine, itaconic acid, acidic pH) impacted the polarization fate and immunosuppressive functions of TAMs, thus possibly resulting in immune tolerance and treatment resistance in GB (for review, see Won et al, 2019). Hence, tolerance can be reversed at both the promoters and enhancers of tolerized genes involved in metabolism and lipid biosynthesis, leading to transcriptional programs that rewired the intracellular signaling of innate immune cells thus increasing the capability of macrophages to respond to stimulation (for review see, Locati et al, 2020).…”

Metabolic Regulation of Myeloid-Derived Suppressor Cell Function in Cancer

“…MDSCs upregulate the expression of cationic amino acid transporter 2 (CAT2) in the TME, which increases the uptake of l-Arg [55]. l-Arg is depleted by MDSCs expressing ARG1, iNOS and CAT2, which impairs the T cell immune response [56]. Moreover, blocking CAT2 reverses the immunosuppressive activity of MDSCs [55].…”

“…eADO is generated from ATP through dephosphorylation by the ectoenzymes ectonucleoside triphosphate phosphohydrolase 1 (ENTPDase1/CD39) and ecto-5'-nucleotidase (Ecto5'NTase/CD73), which are highly expressed in MDSCs undergoing metabolic reprogramming [56]. The upregulation of these enzymes on MDSCs is induced by TGF-β-mTOR-HIF-1 signaling and has been reported in peripheral blood and tumor tissues from non-small cell lung cancer (NSCLC) patients [87].…”

“…As mentioned above, MDSCs induce immune cell apoptosis and blunt anti-tumor responses by depleting amino acids, generating substantial amounts of ROS and reactive nitrogen species (RNS) and digesting ATP into ADO, thereby accelerate tumor growth ( Figure 4) [56,84,88,95]. In addition, MDSCs inhibit the expression of l-selectin (CD62L) on T cells by binding with ADAM metallopeptidase domain 17 (ADAM17) on the T cell surface, resulting in an impact on lymphocyte homing [96,97].…”

“…The most direct targeted MDSC therapy is depletion of MDSCs. At present, there are several kinds of chemotherapy that can effectively eliminate MDSCs and enhance antitumor activity, mainly by low doses of 5-fluorouracil (5-FU), gemcitabine, cyclophosphamide, and paclitaxel [56,120]. Compared to gemcitabine, 5-FU is more effective and selective in reducing the number of MDSCs in the spleen and tumor sites of tumor-bearing mice [121].…”