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. Author manuscript; available in PMC: 2019 Oct 1.
Published in final edited form as: Semin Cancer Biol. 2018 Jun 20;52(Pt 2):107–116. doi: 10.1016/j.semcancer.2018.06.002

Figure 2. Metabolic competition in the tumor microenvironment.

Figure 2.

Left: Metabolic changes during T-cell development, activation, and differentiation. Quiescent Tn cells rely primarily on FAO and OXPHOS, but change to glycolysis for rapid proliferation when activated. Upon further differentiation TH1, TH2 and TH17 cells remain glycolytic, while Treg and Tm cells switch back to FAO and OXPHOS. Unlike LPS stimulated Mstim macrophages that are characterized by a primarily glycolytic metabolism, IL4 stimulated Msupp macrophages are characterized by an oxidative metabolism. Right: Intratumoral competition for metabolites. Immune cell function in the tumor microenvironment is strongly regulated by the oxygen and nutrient availability. Poorly perfused areas can induce a hypoxic response, stimulating glycolysis and lactate dependent acidification. These environmental changes affect macrophage polarization and immune cell function. Lactate as by-product of glycolysis directly suppresses CTLs and DCs, but can can be used as carbon source for Treg cells, promoting an immune suppressive tumor microenvironment. In addition to tumor cells, several immune cells including CTLs, Mstim macrophages (regulated by a REDD1 dependent hypoxia response), and DCs rely on glycolysis, making them compete for the available glucose. Other nutrients such as the amino acids L-arginine and tryptophan are also subjected to cellular competition. Several intratumoral cell types are L-arginine auxotroph, and both tumor cells and CTLs are depending on tryptophan for their function. Increased IDO activity in tumors results in tryptophan depletion and formation of the immune suppressive kynurenine, rendering the tumor microenvironment immunosuppressive. Arg1, arginase 1; CTL, cytotoxic T-lymphocyte; DC, dendritic cell; FAO, fatty acid oxidation; IDO, Indolamine 2,3- diogygenase; IL4, interleukin 4; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; Mstim, Immune stimulatory macrophage, Msupp, Immune suppressive macrophage OXPHOS, oxidative phosphorylation; PFKFB3, 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3; Teff, Effector T-cell; TH, T-helper cell; Tn, naive T-cell; Tm, mature T-cell; Treg, regulatory T-cell; VEGF, vascular endothelial growth factor.