Lipid Metabolic Pathways Confer the Immunosuppressive Function of Myeloid-Derived Suppressor Cells in Tumor

Abstract

Myeloid-derived suppressor cells (MDSCs) play crucial roles in tumorigenesis and their inhibition is critical for successful cancer immunotherapy. MDSCs undergo metabolic reprogramming from glycolysis to fatty acid oxidation (FAO) and oxidative phosphorylation led by lipid accumulation in tumor. Increased exogenous fatty acid uptake by tumor MDSCs enhance their immunosuppressive activity on T-cells thus promoting tumor progression. Tumor-infiltrating MDSCs in mice may prefer FAO over glycolysis as a primary source of energy while treatment with FAO inhibitors improved anti-tumor immunity. This review highlights the immunosuppressive functions of lipid metabolism and its signaling pathways on MDSCs in the tumor microenvironment. The manipulation of these pathways in MDSCs is relevant to understand the tumor microenvironment therefore, could provide novel therapeutic approaches to enhance cancer immunotherapy.

TIPE2 specifies the functional polarization of myeloid-derived suppressor cells during tumorigenesis

“…In mice, MDSCs are defined as cells expressing both Gr1 and CD11b markers, which can be further divided into two subpopulations: granulocytic (G)-MDSCs (CD11b + Ly6G + Ly6C low ) and monocytic (M)-MDSCs (CD11b + Ly6G − Ly6C high ). In humans, G-MDSCs are defined as CD11b + CD14 − CD15 + or HLA-DR −/low CD33 + CD14 −/low CD66b + , and M-MDSCs as CD11b + CD14 + HLA-DR −/low CD15 − or HLA-DR −/low CD33 + CD14 + CD66b − (Veglia et al, 2018;Yan et al, 2019). Despite their significance in cancer and inflammatory diseases, MDSCs remain one of the least understood subsets of leukocytes.…”

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

“…Moreover, tumor-derived lactate has been suggested to directly impair the cytotoxic function of NK and T cells and can control MDSC development and increase cell numbers [206][207][208]. Tumor-associated MDSCs were shown to adapt lipid metabolism as fuel via the upregulation of lipid uptake and mitochondrial fatty acid oxidation to enhance their inhibitory cytokine production in cancer [209,210]. Yet, it is still not fully understood what specific regulatory factors facilitate MDSC metabolic adaption shift from glycolysis to mitochondrial FAO for controlling their immunoinhibitory role in the tumor milieu.…”

Connections between Metabolism and Epigenetic Modification in MDSCs

“…Tumor-invasive MDSCs uses fatty acid oxidation (FAO) as its significant source of ATP [ 46 ]. Moreover, FAO is the main metabolic fuel for producing inhibitory cytokines, and MDSCs rely on FAO to play an immunosuppressive role [ 47 , 48 ]. After tumor invasion, MDSCs increased fatty acid intake and activated FAO, leading to increased mitochondrial biosynthetic, up-regulated key enzymes of FAO, and increased oxygen consumption rate.…”