Table 3 Metabolic changes in immune cells during cancer and biofilm infection

Neutrophils

Neutrophil metabolism is poorly defined in the sense of cancer, and the metabolism of neutrophil-specific subgroups (i.e., N1 or N2) is understudied. In the sense of inflammation, neutrophils need an improved flow of glycolysis and pentose phosphate metabolism (PPP) to support nucleotide synthesis, respiratory bursting, and Neutrophil extracellular trap (NET) development, with minimal criteria for the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and fatty acid synthesis (FAS)

Glucose absorption, glycolysis, and metabolic change to PPP are significant for neutrophil netting sequesters circulating tumor cells and promoting metastases. The data provide some suggestions about how the metabolic shift in neutrophils by controlling functions such as NETs can lead to cancer development (Biswas 2015)

Together, tumor development and the acquisition of immunosuppressive neutrophils are concurrent with a complex development of their metabolism and nutrient utilization, spanning from glucose-fueled glycolysis and OXPHOS to fatty acid-fueled Fatty acid oxidation (FAO) in the initial and end stages, respectively (Riera-Domingo et al. 2020)

It has been found this diminished hypoxic levels of oxygen result in diminishing neutrophil killing ability and because this ability is mediated by the formation of reactive oxygen species (ROS) from oxygen (Jesaitis et al. 2003, 2018; Mandell 1974). Also, suppose this hypoxic situation is continued. In that case, neutrophils will be impaired in producing ROS like hypochlorous acid and hydrogen peroxide, causing impairment of the neutrophil's ability to eliminate and control biofilm infection (Wu et al. 2018)

PMNs in the cystic fibrosis (CF) airway of patients has increased the generation of specific metabolic and stress pathways such as CD39, CD114, C–X–C motif chemokine receptor 1 (CXCR4), as well as Receptor for Advanced Glycation Endproducts (RAGE) (Makam et al. 2009). In this regard, it has been noted that a shift in the formation of their nutrient transporters influences the inorganic phosphate and glucose transports that are part of their adaptation to the airway of CF patients (2013)

Of note, about of anaerobic situation in the mucus of CF patients, Kolpen et al. (Kolpen et al. 2010) hypothesized that the respiratory burst of the polymorphonuclear leukocytes (PMNs) involves oxygen consumption. The interactions between PMNs and microorganisms can enhance oxygen consumption because of extra respiration during phagocytosis by the respiratory burst resulting from the electron reduction of oxygen by NADPH oxidase to O-2 (Baldridge and Gerard 1933; Babior et al. 1976)

Macrophage

Throughout tumor initiation, inflammatory macrophages by glycolytic change, HIF1a (Hypoxia Inducible Factor 1 Subunit Alpha) induction, and blocked OXPHOSP mediate NO (nitric oxide), ROI, IL-1b, and TNF expressions to promote genetic instability cancer-related inflammation that contributes to tumorigenesis (Biswas 2015)

The HIF1a-induced expression of the VEGFA angiogenic molecule is also seen. In TAMs of advanced tumors, activation of AMP-activated protein kinase (AMPK) through nutrient deprivation, lactate accumulation, and Th2-derived IL-4 (activates c-Myc, p53, STAT6, PGC1b), and activated PKM2 suppresses glycolysis while up-regulating OXPHOSP. This induces immunosuppressive macrophages that stimulate tumor development. Changes in the metabolism of amino acids, iron, and facts that lead to this mechanism are often suggested (Biswas 2015)

Ammons et al. (2017), via metabolomics by 1D 1H Nuclear Magnetic Resonance (NMR) along with immunologic evaluations, showed substantial overlap between the metabolic profile driving macrophage polarization either into the M1 phenotype or the M2 phenotype and P. aeruginosa biofilm included crucial metabolic pathways that modulate immunomodulation in macrophages like shifts between the PPP and TCA cycle and amino acid metabolism. They found that exposure of non‐polarized macrophages to small metabolites from planktonic- and biofilm mode of P. aeruginosa resulted in distinct metabolic pathways involved in macrophage immunomodulation include increased glycolysis, uncoupling of the TCA cycle, and selective uptake and metabolism of amino acids Prendergast et al. (2017). Taken together, they found that P. aeruginosa biofilms relevant to specific pathological influences toward macrophages via coordinated metabolic interplays, which cause immune polarization and can involve deviation from the usual healing process of wound and expansion of a chronic host wound Prendergast et al. (2017)

The inflammatory status of leukocytes is associated with their metabolic situation. In this regard, in a study by Yamada et al. (Yamada et al. 2020), monocytes associated with biofilm show a metabolic favoring to OxPhos and less aerobic glycolysis for prompting their anti-inflammatory role that causes persistence of S. aureus biofilm

Fuchs et al. (2020) found some metabolic pathways that are differentially increased in planktonic- and biofilm-exposed macrophages, such as purine biosynthesis glycolysis, branched-chain amino acid catabolism, inositol phosphate metabolism, as well as glycerol metabolism (Fuchs et al. 2020). Besides, these metabolic patterns show that biofilm-exposed macrophages have a hyper-inflammatory metabolic profile, diminished glycerol metabolism, and increased catabolism of amino acids and lactate compared to the planktonic exposed macrophages (Fuchs et al. 2020)

T cells

High expression of the glycolysis pathway in tumor cells reduces amino acids and nutrients and disrupts T cells' antitumor function (Biswas 2015). Under these conditions, as Treg cells rely more on the FAO than glycolysis, they expand and modulate their immune system (Macintyre et al. 2014; Noman et al. 2014). Also, lactate produced in tumor cells similar to the kynurenine (an amino acid metabolic product) suppresses T cells' antitumor activity and at the same time increases the Treg cells' (Siska and Rathmell 2015). Besides, the HIF1a produced by tumor cells increases Treg cell expansion and the induction of programmed death-1-ligand 1 (PD-L1) (Noman et al. 2014; Ben-Shoshan et al. 2008)

The decline of extracellular amino acids (through tumor absorption and other cell types), lactate aggregation, and nutritional starvation AMPK activation prevents T-cell receptor (TCR) signaling and downstream glycolysis (indicated by red T-symbol) in T-cells (e.g., CD8 ]+ cytotoxic T-cells). This resulted in the repression of the propagation and action of the effector. Inhibitory effect of AMPK glycolysis, stimulation of OXPHOS and FAO, and microenvironment-derived tumor stimuli (e.g., Transforming growth factor-beta (TGF-β), Interleukin 10 (IL-10), Kyn, and hypoxia) instead facilitate the growth of regulatory T cells (Tregs). This encourages immune evasion and tumor development (Biswas 2015)

Not determined

Dendritic cell

Tumor-associated dendritic cells (TADCs) encounter tumor-derived Damage-associated molecular patterns (DAMPs) and hypoxia to upregulate glycolysis through initial TBK1-IKKε and/or later PI3K-AKT-HIF1a pathway. HIF1a impairs DC maturation and raises A2b and NO production (which inhibits OXPHOSP). Adenosine-A2b interaction causes immunosuppressive and pro-tumor cytokines. Rising tumor gradually results in nutrient deficiency that triggers AMPK in TADCs. This, along with lactate aggregation, contributes to potential glycolysis inhibition and improved control of OXPHOSP in TADCs. The absorption of amino acids from the tumor microenvironment, metabolism, and MSR1-mediated lipid aggregation further facilitates immunosuppressive activities to help tumor development (Biswas 2015)

Not determined

MDSCs

Although the critical role of nitrogen metabolism in the control of immunomodulatory activities of MDSCs in tumor situations is well-founded, very little is understood about the other metabolic processes in such cells. Enhanced carbon metabolism (glycolysis, glutaminolysis, and TCA activity) and its crosstalk with arginine metabolism were observed during MDSC maturation. However, its association with both AMPK and Sirtuin (SIRT) enhanced expression, which is considered to interact with glycolysis, requires clarity. Increased fatty acid absorption and the FAO have also recently been shown to control tumor infiltration MDSC's (Hammami et al. 2012; Liu et al. 2014; Hossain et al. 2015)

Not determined