Energy metabolism manipulates the fate and function of tumour myeloid-derived suppressor cells

Abstract

In recent years, a large number of studies have been carried out in the field of immune metabolism, highlighting the role of metabolic energy reprogramming in altering the function of immune cells. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a large array of pathological conditions, such as cancer, inflammation, and infection, and show remarkable ability to suppress T-cell responses. These cells can also change their metabolic pathways in response to various pathogen-derived or inflammatory signals. In this review, we focus on the roles of glucose, fatty acid (FA), and amino acid (AA) metabolism in the differentiation and function of MDSCs in the tumour microenvironment, highlighting their potential as targets to inhibit tumour growth and enhance tumour immune surveillance by the host. We further highlight the remaining gaps in knowledge concerning the mechanisms determining the plasticity of MDSCs in different environments and their specific responses in the tumour environment. Therefore, this review should motivate further research in the field of metabolomics to identify the metabolic pathways driving the enhancement of MDSCs in order to effectively target their ability to promote tumour development and progression.

Metabolic Regulation of Myeloid-Derived Suppressor Cell Function in Cancer

“…l-arginine (l-Arg) is a conditionally essential amino acid that is necessary for the activity of T lymphocytes. The catabolism of l-Arg is catalyzed by ARG1 or iNOS into urea and l-ornithine (Orn) or NO and l-citrulline [53]. MDSCs overexpress ARG1 under the stimulation of Th2 cytokines, such as IL-4, IL-10 and IL-13, while overexpress iNOS under the induction of Th1 cytokines, such as TNF-α, IL-1 and IFNγ [54].…”

Carbohydrate and Amino Acid Metabolism as Hallmarks for Innate Immune Cell Activation and Function

“…A metabolic hallmark of MDSCs is the increase of cellular amino acid metabolism. MDSCs control immune tolerance using different mechanisms, one of which is by depleting metabolites from the extracellular space, such as arginine, tryptophan, and cysteine, and preventing their uptake by T cells [199]. Metabolic conversion of arginine via either Arg1 or iNOS is the key mechanism strongly associated with MDSC immunosuppressive property.…”

Connections between Metabolism and Epigenetic Modification in MDSCs

“…GR signaling inhibits HIF-1α and HIF-1α -dependent glycolysis in MDSCs, thereby promoting immunosuppressive activity of MDSCs [ 33 ]. Thirdly, mTOR signaling activates HIF-1α-mediated transcription under hypoxia conditions, leading to increased glucose, lactate transporter, and glycolytic enzyme expression levels, as well as reduced mitochondrial oxygen consumption, which in turn mediates the transition from OXPHOS to glycolysis [ 5 , 34 ]. The deficiency of mTOR or mTOR-targeted immunosuppressive drug Rapamycin (RPM) can significantly inhibit the glycolytic pathway of MDSCs and reduce the inhibitory activity of MDSCs [ 18 , 35 ].…”

“…PMN-MDSCs and neutrophils have the same phenotype and morphological characteristics, while M-MDSCs are similar to monocytes and have high plasticity. The differentiation of M-MDSCs into macrophages and DCs is influenced by the tumor microenvironment (TME) [ 4 , 5 ]. Considerable evidence shows that MDSCs negatively regulate the immune response in cancer [ 6 , 7 ] and other diseases such as aging [ 8 ] and inflammation [ 9 ].…”