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Review
. 2021 Aug;7(8):700-713.
doi: 10.1016/j.trecan.2021.04.007. Epub 2021 May 19.

Metabolic Plasticity of Neutrophils: Relevance to Pathogen Responses and Cancer

Thomas Rogers  1 , Ralph J DeBerardinis  2
Affiliations
Review

Metabolic Plasticity of Neutrophils: Relevance to Pathogen Responses and Cancer

Thomas Rogers et al. Trends Cancer. 2021 Aug.

Abstract

Neutrophils, the most abundant leukocyte population in humans, constantly patrol the body for foreign cells, including pathogens and cancer cells. Once neutrophils are activated, they engage distinct metabolic pathways to fulfill their specialized antipathogen functions. In this review, we examine current research on the metabolism of neutrophil differentiation and antipathogen responses. We also discuss how tumor-associated neutrophils (TANs) can be educated by cytokines and by the nutrient-restrictive milieu of the tumor microenvironment (TME) to suppress antitumor immunity, promote cancer progression, and contribute to biological heterogeneity among tumors. Last, we discuss the clinical implications of circulating neutrophils and infiltrating TANs and consider how targeting TAN metabolism may synergize with cancer immunotherapy.

Keywords: immunotherapy; metabolism; metastasis; neutrophils; tumor microenvironment.

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Conflict of interest statement

Declaration of Interests R.J.D. is a scientific advisor for Agios Pharmaceuticals and Vida Ventures. T.JR has no competing interests to declare.

Figures

Figure 3.
Figure 3.
Within the TME, rapidly dividing tumors cells may outcompete immune and stromal cells for essential nutrients, forcing metabolic adaptations for cell function and survival. In the TME, if glucose availability declines, alternative nutrients must supply the critical pathways that allow tumor-associated neutrophils (TANs) to support tumor progression. TANs utilize fatty acid oxidation to power immunosuppression of antitumor T cells [39]. Tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) also promotes expression of fatty acid transport protein 2 (FATP2), through which TANs take up fatty acids, such as arachidonic acid, for prostaglandin-mediated inflammatory signaling [40]. TANs uniquely express cell surface receptor lectin-type oxidized low-density lipoprotein (OxLDL) receptor-1 (LOX-1), which may stimulate NADPH oxidase [41]. In glucose-depleted conditions, c-KIT+ and low-density TANs exhibit increased mitochondrial respiration and are sensitive to either electron transport chain or fatty acid oxidation inhibitors, such as rotenone/antimycin A and etomoxir, respectively [31,35]. Furthermore, in some glucose-limited settings, NADPH oxidase activity can be supported by NADPH production outside of the pentose phosphate pathway (PPP), likely through either malic enzyme (ME) or isocitrate dehydrogenase (IDH) [35]. Pharmacological inhibition of glutamine catabolism by JHU-083 in the TME decreases TAN abundance, positioning glutamine as a regulator of TAN survival [38]. TANs also secrete metabolites and metabolic enzymes to suppress antitumor immunity. They directly suppress T cell inflammatory signaling by releasing proteases, NADPH oxidase-derived reactive oxygen species (ROS) and reactive nitrogen species produced by inducible nitric oxide synthase (iNOS) [37,103]. They also deplete the local environment of arginine, an essential nutrient for T cell function, by secreting arginase-1 (ARG1) [37]. TANs can also suppress cytotoxic T cell function through the release of neutrophil extracellular traps (NETs), which can form a physical barrier between tumor cells and antitumor T cells, further disrupting antitumor immunity [104]. Abbreviations: α-KG, α-ketoglutaric acid; PGE2, prostaglandin E2, NO, nitric oxide; Rot/AA, rotenone and Antimycin A; TCA, tricarboxylic acid, electron transport chain inhibitors.
Figure 1.
Figure 1.. Metabolism of Granulopoiesis.
Granulopoiesis is a highly regulated differentiation process, leading to the generation of mature neutrophils from hematopoietic stem cells [4]. Granulocyte colony-stimulating factor (G-CSF) is the major cytokine promoting neutrophil differentiation in the bone marrow and also regulates salvage NAD+ synthesis through upregulation of nicotinamide phosphoribosyltransferase (NAMPT) [12]. This increase in NAD+ production coincides with engagement of oxidative phosphorylation (OXPHOS) as a result of increased oxygen availability. Improved OXPHOS function also occurs due to suppression of pyruvate dehydrogenase kinase (PDK), leading to the conversion of pyruvate to acetyl-CoA by pyruvate dehydrogenase (PDH) [9]. Regulation of adenylate nucleotides (AMP, ADP, and ATP) in the mitochondria by adenylate kinase-2 (AK2) is also necessary for proper granulopoiesis, wherein mutations in the gene encoding AK2 lead to reticular dysgenesis, a rare genetic disorder resulting in severe combined immunodeficiency [10]. Autophagy also supports mitochondrial respiration during granulopoiesis [14]. Emergency granulopoiesis by pathogen-derived byproducts also influences mature neutrophil metabolism through Toll-like receptors (TLRs) to engage the pentose phosphate pathway (PPP) and prime neutrophils for an oxidative burst once they reach the site of infection. In a similar fashion, tumor microenvironment (TME)-derived cytokines, such as G-CSF, chemokine (C-X-C motif) ligand 1/2 (CXCL1/2), or interleukin 17 (IL-17), can not only skew differentiation of hematopoietic cells toward granulocyte precursors and mature neutrophils [89], but also promote tissue-specific recruitment to support tumor progression and metastasis [–92]. More research is needed to understand whether these TME-derived cytokines manipulate granulopoiesis-related metabolism or metabolically prime mature neutrophils toward an N2, protumor phenotype even before reaching a primary tumor or metastatic sites. Abbreviation: GCSFR, granulocyte colony-stimulating factor receptor.
Figure 2.
Figure 2.. Metabolic Requirements for Pathogen Response.
During infection, microbial byproducts are detected by neutrophils in the bone marrow, prompting granulopoiesis. Upon arriving to the site of infection, neutrophils engulf pathogens into the phagolysosome. Once engulfed, superoxide and other reactive oxygen species (ROS) are produced by the NADPH oxidase protein complex within the phagolysosome in a process termed the ‘oxidative burst’ [4]. NADPH, the substrate of NADPH oxidase, is produced by glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the oxidative branch of the pentose phosphate pathway (PPP), and possibly by other enzymes, including NADPH-dependent isoforms of isocitrate dehydrogenase and malic enzyme. Shunting of carbons into the PPP is thought to be the predominant source of cytosolic NADPH in these cells. When glucose is limiting, neutrophils can maintain ATP production and carbon flux through the PPP by breaking down glycogen [18]. Glutamine uptake has also been shown to promote NAPDH oxidase activity in neutrophils, but whether this effect involves glutamine-dependent NAPDH production has not been fully examined. To suppress pathogen dissemination, neutrophils also secrete neutrophil extracellular traps (NETs), comprising granule proteins and DNA fragments. These NETs bind bacteria and degrade viral and bacterial proteins. Metabolically, similar to the ‘oxidative burst’, glycolysis and G6PD expression support NET formation [20]. Abbreviations: α-KG, α-ketoglutaric acid; GA3P, glyceraldehyde 3-phosphate; GLS, glutaminase; OAA, oxaloacetic acid; 3PG, 3-phosphoglyceric acid.
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