Metabolic influence on the differentiation of suppressive myeloid cells in cancer

Abstract

New evidences indicate that the metabolic instruction of immunity (immune metabolism) results from the integration of cell metabolism and whole-body metabolism, which are both influenced by nutrition, microbiome metabolites and disease-driven metabolism (e.g. cancer metabolism). Cancer metabolism influences the immunological homeostasis and promotes immune alterations that support disease progression, hence influencing the clinical outcome. Cancer cells display increased glucose uptake and fermentation of glucose to lactate, even in the presence of completely functioning mitochondria. A major side effect of this event is immunosuppression, characterized by limited immunogenicity of cancer cells and restriction of the therapeutic efficacy of anticancer immunotherapy. Here, we discuss how the metabolism of myeloid cells associated with cancer contributes to the differentiation of their suppressive phenotype and therefore to cancer immune evasion.

Inflammation and Pancreatic Cancer: Focus on Metabolism, Cytokines, and Immunity

“…The majority of obese patients present a reduced release of the anti-inflammatory adipokine adiponectin and an increased release of the pro-inflammatory adipokine leptin. Moreover, a shift from the M2 anti-inflammatory to the M1 pro-inflammatory macrophages that infiltrate the adipose tissue, triggers the release of pro-inflammatory cytokines, mainly tumor necrosis factor alpha (TNFα) and interleukin (IL)-6 [30]. The metabolic syndrome might also enhance cancer risk through the increased release of the vascular endothelial growth factor (VEGF), a pro-angiogenetic cytokine, but also through the pro-proliferative effects of insulin, the levels of which are, in most cases, increased consequent to peripheral insulin resistance.…”

“…Microbial structural components and products may act on local epithelial cells, and at distant sites. Fatty acids, found in excess in patients with the metabolic syndrome, might impact on inflammatory cells, favoring the shift towards an immunosuppressive phenotype that allows for tumor cells to escape from immune control [30]. For example, butyrate, an SCFA, may be an energy source for colonocytes contributing to their renewal, but it favors the increased expression of the Foxp3 boosting T reg function [37].…”

Lipid Metabolism and Cancer Immunotherapy: Immunosuppressive Myeloid Cells at the Crossroad

“…In contrast to the anti-inflammatory role of PPARγ in IL-4-polarized macrophages, the enhanced PPARγ signalling in cancer-associated PMN-MDSCs decreases the lysosomal acid lipase (LAL), generating reduced ROS production and impairing cancer cell proliferation and metastasis [ 169 ]. Additional evidence showed that polyunsaturated fatty acids (PUFA), such as linolenic acid (ω-3) and (ω-6), as well as a fish oil-based diet (rich in ω-3 PUFA), are able to induce accumulation of MDSCs both in vitro and in vivo [ 170 ]. Recent in vitro experiments showed that treatment of the myeloid suppressor cell line MSC-2 with sodium oleate and lineolate (unsaturated fatty acids), but not with stearate (saturated FA), increases intracellular lipid droplet formation paralleled by potent suppressive functions on activated T cells [ 171 ].…”

Implications of metabolism-driven myeloid dysfunctions in cancer therapy

“…79 This metabolic setting influences the crosstalk between tumor cells and tumor-infiltrating immune cells, creating competition for essential nutrients (glucose, in particular) and immunosuppression, which consequently hinder the therapeutic efficacy of anticancer immunotherapy. 80 TME metabolism requires the cofactor nicotinamide adenine dinucleotide (NAD), which functions in many critical redox processes necessary for cancer cells and immune cells. 81 Based on this, inhibitors of intracellular nicotinamide phosphoribosyltransferase (iNAMPT), the rate-limiting enzyme of NAD production in its salvage pathway, have entered clinical trials for solid and nonsolid tumors due to their ability to lower NAD and ATP levels and interfere with malignant cell growth.…”

“…Consumption of essential amino acids is a classic example of how tumors exploit metabolic pathways to generate molecules endowed with immunomodulatory activities and deplete nutrients essential for T cells. In particular, TAMs and MDSCs express high levels of IDO1, an enzyme that converts tryptophan into its immunosuppressive catabolite Kyn, which is capable of inducing the expansion of regulatory T (Treg) cells, 80 depriving T cells of an essential nutrient 132 and hindering the immunogenicity of DCs. 110 l -arginine depletion is one of the main mechanisms by which MDSCs inhibit antitumoral T cell activity; however, granulocytic (PMN-MDSCs) and monocytic (M-MDSCs) subsets of MDSCs use distinct enzymes or arginine metabolism to generate immunosuppression.…”