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Anderson, G. Tumour Microenvironment and Metabolism. Encyclopedia. Available online: https://encyclopedia.pub/entry/55666 (accessed on 16 April 2024).
Anderson G. Tumour Microenvironment and Metabolism. Encyclopedia. Available at: https://encyclopedia.pub/entry/55666. Accessed April 16, 2024.
Anderson, George. "Tumour Microenvironment and Metabolism" Encyclopedia, https://encyclopedia.pub/entry/55666 (accessed April 16, 2024).
Anderson, G. (2024, February 28). Tumour Microenvironment and Metabolism. In Encyclopedia. https://encyclopedia.pub/entry/55666
Anderson, George. "Tumour Microenvironment and Metabolism." Encyclopedia. Web. 28 February, 2024.
Tumour Microenvironment and Metabolism
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Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3β, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven ‘backward’ conversion of melatonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a crucial co-substrate for initiation of the melatonergic pathway, as well as co-ordinating the interactions of OXPHOS and glycolysis in all cells of the tumour microenvironment. This provides a model of the tumour microenvironment that emphasises the roles of acetyl-CoA and the melatonergic pathway in shaping the dynamic intercellular metabolic interactions of the various cells within the tumour microenvironment. The potentiation of YY1 and GSK3β by O-GlcNAcylation will drive changes in metabolism in tumours and tumour microenvironment cells in association with their regulation of the melatonergic pathway. 

cancer tumour microenvironment aryl hydrocarbon receptor immune melatonin mitochondria acetyl-CoA

1. Introduction

Recent work on the pathophysiology of the severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 in the COVID-19 pandemic has highlighted the co-ordinating role of the aryl hydrocarbon receptor (AhR), including in the suppression of CD8+ T cell and natural killer (NK) cell cytotoxicity [1]. A dysregulated inflammatory response, coupled to suppression of the antiviral and anticancer responses of CD8+ T cells and NK cells has emerged as a commonality in the altered immune responses evident in SARS-CoV-2 infection and the tumour microenvironment [1]. AhR activation in CD8+ T cells and NK cells is one of a number of processes contributing to ‘exhaustion’ in these cells, and thereby to the immune suppression that is evident in the tumour microenvironment of almost all cancers. Other pathways also induce an ‘exhausted’ phenotype, including cancer cell release of transforming growth factor (TGF)-β, the activation of the adenosine A2A receptor (A2Ar) and the induction of the cyclooxygenase (COX)2-prostaglandin (PG)E2 path leading to the activation of the PGE2 receptor, (EP)4. Antagonists of these specific ‘immune checkpoint’ pathways are widely utilised in the treatment of cancer patients, often adjunctive and with relatively limited clinical efficacy [2]. Other inhibitors of NK cells, include NKG2A, inhibitory killer cell Ig-like receptors (KIRs), and CD96, whereas NKG2D, CD16, NKp30, NKp44, and NKp46 can activate NK cells. The effects of these inhibitory and activating receptors are classically associated with their differential activation by cancer cell-expressing/released ligands [3]. Overall, a number of factors, including cancer cell derived, can regulate cytolytic cell cytotoxicity and the ‘exhaustion’ associated with immune suppression in the tumour environment.
Partly as a consequence of the limitations of treatment directed towards ‘exhaustion’-inducing pathways, recent work has focussed on the targeting of specific receptors associated with ‘exhaustion’ and which may contribute to this phenotype, especially antagonists of the programmed cell death (PD)-1 receptor and its ligand, PD-L1.

2. Tumour Microenvironment and Immune Suppression: Exhaustion

A number of different cells are evident in the tumour microenvironment, including different types of cancer cells and a range of immune cells, with the interactions of these cells proposed to ultimately drive immune suppression via their regulation of NK cells and CD8+ T cells. Factors associated with the induction of ‘exhaustion’ in CD8+ T cells and NK cells within the tumour microenvironment, include the AhR, TGF-β, CD73 (ecto-5-Nucleotidase), adenosine A2Ar activation, PD-1, and the COX2/PGE2/EP4 pathway. The researchers briefly review the data pertaining to the functioning of these receptors and pathways, and their contribution of an ‘exhausted’ state in cytolytic cells.

2.1. Aryl Hydrocarbon Receptor

The AhR has a number of exogenous and endogenous ligands, including air pollutants, 6-formylindolo[3,2-b]carbazole (FICZ) and the cigarette smoke constituent, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, perhaps more important to its regulation of the cytolytic immune response to viruses and cancers is the induced AhR ligand, kynurenine. Stress and pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-18, tumour necrosis factor (TNF)α, and especially interferon (IFN)γ, increase indoleamine 2,3-dioxygenase (IDO), which takes tryptophan away from serotonin and melatonin synthesis and drives it to the production of kynurenine and kynurenine pathway products. In some cells, tryptophan 2,3-dioxygenase (TDO) is predominantly expressed and likewise converts tryptophan to kynurenine. The cytokine/IDO/kynurenine/AhR pathway is relevant to a wide array of diverse medical conditions, including neuropsychiatric conditions [4][5], as well as all cancers [6].
The cytokine/IDO/kynurenine/AhR pathway is present within cancer cells, with intracellular AhR activation affording protection in cancer cells [7]. As such, an initial increased release of pro-inflammatory cytokines, especially IFNγ, from NK cells in the tumour microenvironment drives IDO induction in cancer cells, leading to intracrine kynurenine activation of the AhR that acts to protect cancer cells. As well as intracrine kynurenine effects, cancer cells also release kynurenine, which activates the AhR on tumour microenvironment cells, including CD8+ T cells and NK cells, thereby inducing an ‘exhausted’ phenotype, concurrent to increasing PD-1 plasma membrane expression [8]. AhR activation also induces the COX2/PGE2/EP4 pathway [9][10], which is an important driver of an ‘exhausted’ phenotype [11]. Consequently, kynurenine activation of the AhR affords protection within cancer cells and acts to induce ‘exhaustion’ in cytolytic cells, with effects involving the upregulation of COX2 and PD-1. AhR activation also induces CD39 and CD73, thereby increasing the conversion of ATP to adenosine [12], allowing AhR activation to raise adenosine levels from different cells of the tumour microenvironment, thereby driving A2Ar activation and contributing to ‘exhaustion’ in NK cells and CD8+ T cells.

2.2. Transforming Growth Factor-β (TGF-β)

TGF-β release, including from tumour cells, can also induce ‘exhaustion’ in CD8+ T cells [13] and NK cells within the tumour microenvironment [14][15]. As well as tumour cells, TGF-β is also released from myeloid-derived suppressor cells (MDSC), tumour-associated M2-like macrophages, gammaDelta (γδ) T cells, mast cells and regulatory T cells (Treg), allowing these cells to contribute to cytolytic cell exhaustion and immune suppression [16][17][18]. Activation of the AhR/COX2/PGE2 pathway in tumours leads to PGE2 release and EP2 and EP4 activation in different cells, in turn increasing TGF-β release, and TGF-β-induced adenosine, from these cells and thereby contributing to cytolytic cell ‘exhaustion’ [19]. As such, the regulation of TGF-β, across cells of the tumour microenvironment is important to the regulation of immune suppression, including following AhR activation. Such AhR effects may then be co-ordinated with decreased melatonin production across cells, leading to the loss of melatonin’s suppression of TGF-β as found not only in cancer cells [20], but also in fibrosis where melatonin’s suppression of TGF-β is a major inhibitor of fibrosis, across different organs and tissues [21][22]. As such, the co-ordinated suppression of melatonin production and raised TGF-β allows AhR activation to heighten TGF-β levels and effects across the various cells of the tumour microenvironment.
Platelets are another important source for TGF-β in the tumour microenvironment, with platelet TGF-β contributing to tumour survival and metastasis [23] as well as the chemoattraction of MDSCs [24]. As AhR activation on platelets increases platelet aggregation and primes platelets for enhanced activation [25], the platelet AhR will be important in the regulation of immune suppression. Melatonin, which is decreased following activation of the cytokine/IDO/AhR path, suppresses platelet activation, suggesting that suppressed melatonin production, both circadian and local, will contribute to processes upregulating platelet TGF-β and its effects [26]. TGF-β can also induce ‘exhaustion’ in cytolytic cells via the upregulation of CD73 and thereby the conversion of adenosine monophosphate (AMP) to adenosine leading to A2Ar activation, as shown in CD4+ T cells [27] and CD8+ T cells [28]. Heightened adenosine production is evident across a number of cells in the tumour microenvironment, highlighting how the dynamic interactions of the array of tumour microenvironment cells can contribute to immune suppression [29].

2.3. Hypoxia/HIF-1α Increases A2Ar, CD73 and CD39

Tumour microenvironment hypoxia is a major driver of adenosine production, via the upregulation of hypoxia-inducible factor (HIF)-1α [30]. HIF-1α increases A2Ar, CD73 and CD39, the latter converting ATP to AMP, thereby increasing adenosine and A2Ar activation across a number of cells in the tumour microenvironment [31]. Consequently, eliminating solid tumour hypoxia by natural blood substitutes and synthetic oxygenation agents have been proposed as routes whereby the hypoxia-HIF-1α-adenosine/A2Ar pathway may be blocked, thereby enhancing immunotherapy-targeted treatments [31].
Notably, melatonin significantly inhibits HIF-1α induction [32], being another route, along with antagonism of the AhR and TGF-β, whereby the suppression of melatonin will contribute to immune suppression driven by adenosine A2Ar activation. Hypoxia/HIF1-α alters OXPHOS and mitochondrial metabolism in tumours by inducing Ku80, which binds and activates the pyruvate dehydrogenase kinase (PDK)1 promoter, thereby acting to inhibit the pyruvate dehydrogenase complex (PDC), in turn inhibiting the PDC conversion of pyruvate to acetyl-CoA, which is crucial to driving OXPHOS, the TCA cycle and the melatonergic pathway [33]. Melatonin degrades and inhibits HIF1-α in tumours, thereby increasing apoptosis [33], again indicating the impact that variations in local melatonin production can have on core tumour regulators [34]. Taking pyruvate away from acetyl-CoA production and driving it to lactate production is an important mediator of key changes in tumour metabolism, as indicated by acetate supplementation leading to tumour cell differentiation under hypoxia [35]. Although, the authors attribute the benefits of acetate supplementation to be mediated by increased chromatin acetylation, it is clear that acetate supplementation would also increase the activation of the melatonergic pathway, TCA cycle and OXPHOS. The relevance of the HIF1-α/Ku80/PDK1 pathway to alterations in metabolism of other cells in the tumour microenvironment will be important to determine.

2.4. Adenosine A2Ar, mTORC1, OXPHOS and Exhaustion

A2Ar activation is proposed to mediate cytolytic cell suppression via the cyclic adenosine monophosphate (cAMP)/protein kinase (PK)A/phosphorylated cAMP response element binding protein (pCREB) pathway and mammalian target of rapamycin complex 1 (mTORC1) complex suppression (via S6 phosphorylation), with this leading to impaired T cell receptor (TCR)-dependent extracellular-signal-regulated-kinase (ERK) phosphorylation in human CD8+ T cells [36]. The mTORC1 complex is crucial to glycolysis upregulation in CD8+ T cells and NK cells and is upregulated by a number of processes/factors, including HIF-1α, c-MYC and especially the system L neutral amino acid transporter (LAT)1, encoded by SLC7A5. Upregulated glycolysis is required for all immune cells to become activated, including CD8+ T cells and NK cells [37]. The inhibition of the mTORC1 complex and the prevention of LAT1 upregulation, prevents the necessary induction of glycolysis and therefore the increased metabolism and amino acid availability that is required for a shift to a cytotoxic cellular phenotype. Factors, such as A2Ar activity, which impact on mTORC1 activation and LAT1 upregulation, are therefore crucial in determining whether cytolytic cells shift to a cytotoxic phenotype or state of ‘exhaustion’ [38][39].

2.5. Acetyl-CoA, AhR and AMPK

A deficiency in AMP-activated protein kinase (AMPK) is long appreciated to contribute to exhaustion in CD8+ T cells [40], including by increasing PD-1 [41]. AMPK also inhibits acetyl-CoA carboxylase (ACC), thereby increasing acetyl-CoA and ATP synthesis [42]. Notably, AMPK is regulated by the AhR-driven degradation of Synphilin-1, thereby decreasing AMPK and therefore preventing the AMPK suppression of ACC [43]. As such, the AhR degradation of Synphilin-1, leading to AMPK inhibition and ACC disinhibition is another route whereby the AhR can attenuate acetyl-CoA levels, thereby lowering acetylated-COX2, acetylated-Raptor and the melatonergic pathways, with consequences for the mTORC1 complex induction of cMYC, LAT1 and glycolysis. It will be important to determine as to whether the acetylation of COX2 modulates the ability of the AhR to suppress Synphilin-1. Similar processes are evident in NK cells.
AMPK inhibition underpins the association of obesity and type II diabetes with many cancers. High glucose levels inhibit AMPK, coupled to MHC class I chain-related protein A/B (MICA/B) suppression [44], thereby contributing to NK cell ‘exhaustion’ in obesity and type II diabetes. Metformin, commonly used to treat type II diabetes, can upregulate CD8+ T cell cytotoxicity via an increase in AMPK, as well as by suppressing adenosine production in MDSCs, via the inhibition of CD39 and CD73, and therefore A2Ar activity in cytolytic cells [45]. As such, the AMPK interaction with nutrient-sensing, mTOR and metabolism may all be subject to AhR regulation, with important effects mediated by the suppression of acetyl-CoA levels.
Overall, the interactions of the AhR with regulators of PDC-regulated acetyl-CoA provides a metabolic framework that integrates wider bodies of data pertaining to the induction of ‘exhaustion’ in CD8+ T cells and NK cells in the tumour microenvironment, with effects mediated via alterations in the dynamic metabolic interactions of tumour microenvironment cells.

3. Integrating Wider Bodies of Data: Ageing, Sirtuins, Circadian and Cell-Specific Factors

3.1. MDSCs, Dendritic Cells, Metabolism and Acetyl-CoA

As noted, alterations in other cells in the tumour microenvironment can modulate CD8+ T cell and NK cell cytotoxicity, including via variations in fluxes from MDSC, tumour-associated M2-like macrophages, γδT cells, mast cells, Treg, neutrophils and dendritic cells, allowing these cells to contribute to the regulation of cytolytic cell exhaustion and immune suppression [16][17][18][46]. The suppression of tuberous sclerosis complex subunit 1 (TSC1) in dendritic cells leads to mTOR disinhibition and consequent ACC upregulation, thereby lowing acetyl-CoA levels and attenuating the epigenetic imprinting of MHC-1 by acetyl-CoA regulated histone acetylases [47]. Such changes in dendritic cells compromise their induction of activated CD8+ T cells and highlight the importance of acetyl-CoA to dendritic cell regulation of CD8+ T cells [47] and NK cells [48]. As with other immune cells, variations in glycolysis and OXPHOS are crucial to dendritic cell function, with consequences for the interactions of innate and adaptive immunity [49].
The AhR is expressed on dendritic cells where it significantly modulates dendritic cell function, indicating that AhR ligand upregulation will be an important modulator of all immune cells and their interactions in the tumour microenvironment [50]. This is also exemplified in MDSCs, where the AhR induces metabolic activation, via increased glycolysis and maintained OXPHOS, leading to heightened immune suppression [51]. This suggests that the release of kynurenine by tumours will have some co-ordinating effect on the metabolism and patterning of interactions among cells of the tumour microenvironment, with effects that may ultimately be associated with variations in the cytotoxic response of NK cells and CD8+ T cells. The concurrent regulation of acetyl-CoA and the melatonergic pathway within the cells of the tumour microenvironment clearly requires investigation.

3.2. Ageing, Acetyl-CoA, AhR and Sirtuins

SIRT1 regulates dendritic cell, NK cell and CD8+ T cell function, as well as the function of iNKT lymphocytes [52] and MDSC [53]. The loss of SIRT1 markedly upregulates ACC, decreasing acetyl-CoA and dramatically altering dendritic cell function [54]. As SIRT1, like melatonin, decreases over age, an ageing-associated decrease in SIRT1 will contribute to ACC elevations that lower acetyl-CoA, leading to a dysregulation in the co-ordination of glycolysis and OXPHOS [55]. Notably, the AhR increases with age and is proposed to be a major driver of ageing and ageing-associated medical conditions, including most cancers [56], as well as increases in ageing-associated fatality risk to SARS-CoV-2 infection and other age-linked medical conditions [1]. AhR activation also decreases SIRT1 in immune cells [57]. This is important to the regulation of mitochondria-located SIRT3 via the SIRT1 deacetylation and activation of SIRT3, and therefore mitochondrial function and SOD2 levels. Overall, ageing-associated changes in sirtuins, AhR, SOD2, and acetyl-CoA may be intimately linked to suboptimal cytolytic cell function, as an aspect of the changes underpinning immunosenescence, and contributing to alterations in the functioning and interactions of the cells of tumour microenvironment. Ageing-associated changes in sirtuins, acetyl-CoA, the melatonergic pathway and metabolism therefore modulate the function and interactions of the cells of the tumour microenvironment.

3.3. Circadian Dysregulation

Many factors dysregulate the circadian rhythm, including an increase in pro-inflammatory cytokines [58], amyloid-beta (Aβ) [59], gut-derived lipopolysaccharide (LPS) and high-mobility group box (HMGB1) [60], as well as circadian disruption associated with shift-work [61]. All of these factors are associated with decreased pineal gland melatonin production. Clinical and preclinical data indicate a role for circadian dysregulation in the aetiology and progression of tumours, with circadian disruption increasing the levels of CSC, proliferation and metastasis [62]. Variations in the circadian rhythm, including pineal melatonin, complicate the dynamic interactions of the cells in the tumour microenvironment [63]. Pineal melatonin upregulates Bmal1/PDC/acetyl-CoA/OXPHOS in immune cells, where under physiological conditions pineal melatonin may act to ‘reset’ the metabolism of immune cells. Consequently, factors acting to suppress pineal melatonin, such as pro-inflammatory cytokines, Aβ, LPS and HMGB1 will modulate the metabolism and interactions of the cells of the tumour microenvironment, adding another layer of complexity. The reciprocal negative interactions of melatonin and the AhR, coupled to the circadian rhythm of the AhR, would indicate that suppressed melatonin will significantly modulate the levels and effects of the AhR in the tumour microenvironment over the circadian rhythm. As such, suppressed pineal melatonin will modulate the AhR influence on the tumour microenvironment, including over the circadian rhythm.
Notably, pineal melatonin upregulates the alpha 7 nicotinic acetylcholine receptor (α7nAChR) levels. The α7nAChR significantly regulates immune cells and mitochondrial function [64], including from vagal ACh, allowing vagal ACh to afford protection against cancer progression via α7nAChR activation [65]. This would indicate that the suppression of pineal melatonin’s induction of the α7nAChR will contribute to alterations in the circadian regulation of the tumour microenvironment. Melatonin, the α7nAChR and the AhR are present on the mitochondria membrane [66], where their interactions will be important to determine. α7nAChR effects are complicated by its uniquely human duplicate, dupα7 (CHRFAM7A), which negatively regulates the α7nAChR. As the α7nAChR and dupα7 are differentially regulated, both genetically and epigenetically, this further complicates the interactions of melatonin, α7nAChR and dupα7 in the regulation of immune cells and mitochondrial function [67]. LPS can differentially regulate the α7nAChR and dupα7 [67], with LPS also inhibiting pineal melatonin, dysregulating immune responses and altering O-linked-N-acetylglucosaminylation (O-GlcNAcylation) [68]. O-GlcNAcylation is a significant regulator of tumours and cells of the tumour microenvironment. Such LPS effects would suggest that gut permeability-associated elevations in LPS may co-ordinate a number of important changes in the tumour microenvironment, including relative α7nAChR and dupα7 levels, with consequences for the circadian regulation of immune cells.

4. Wider Regulators of the Tumour Microenvironment and Immune Suppression

A number of other factors are frequently associated with the regulation of immune suppression in cancers, including yin yang (YY)1, protein phosphatase (PP)2A, glycogen synthase kinase (GSK)3β, ribosomal receptor for activated C-kinase 1 (RACK1) and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Many of these factors have their pro-cancer effects significantly strengthened by O-GlcNAcylation, concurrent to alterations in acetyl-CoA and the melatonergic pathway.

4.1. O-linked-N-Acetylglucosaminylation (O-GlcNAcylation)

O-GlcNAcylation is a form of glycosylation, whereby a monosaccharide, viz O-GlcNAc, is added to a serine or threonine residue of nuclear and/or cytoplasmic protein by O-GlcNAc transferase (OGT). This is readily reversibly by the removal of O-GlcNAc by O-GlcNAcase (OGA). O-GlcNAcylation acts to regulate a wide array of physiological and pathophysiological processes by virtue of its ability to interact with nutrient sensing and metabolism, including via a host of signal transduction and transcription factors.
O-GlcNAcylation and the voltage-dependent anion channel (VDAC)2 are linked to the regulation of the apoptotic threshold during different physiological processes, including on mitochondria during the transfer of astrocyte mitochondria [69] and mitosis [70]. The O-GlcNAcylation of VDAC2 regulates the association of VDAC2 with Bcl-2-like family proteins, such as Bax and Bak, thereby modulating apoptotic susceptibility [71][72]. The O-GlcNAcylation of VDAC2 is therefore a significant determinant of mitochondria survival and presumably function during major physiological processes [73], including tumour survival via the regulation of chemotherapy resistance [71].
O-GlcNAcylation enhances the development, as well as the activation and proliferation of neutrophils, T and B cells, with regulatory effects in macrophages, whilst inhibiting the development and cytotoxicity of NK cells [74]. O-GlcNAcylation significantly regulates many of the transcriptional and translational processes that underpin fast effector CD8+ T cell proliferation, as well as a more limited number of studied proteins in memory-like CD8+T cells [75]. As such, variations in O-GlcNAcylation regulate the function of many cells in the tumour microenvironment, with some distinct and opposing effects in NK cells and CD8+ T cells. The relevance of O-GlcNAc to the regulation and dynamic interaction of cytolytic cells within the tumour microenvironment requires further investigation.

4.2. O-GlcNAcylation and Yin Yang1

The YY1 transcription factor significantly increases tumour cell growth and metastasis [76]. YY1 also induces immunosuppression, including by suppressing IFNγ [77], as well as upregulating PD-1, Lymphocyte-activation gene (Lag)3, and T cell immunoglobulin and mucin-containing domain (TIM)-3, indicating a significant role for YY1 in co-ordinating many of the correlates of ‘exhaustion’ [78]. O-GlcNAcylation increases YY1 stability, thereby stimulating YY1-dependent transcriptional activity, including of AANAT and the melatonergic pathway [79][80][81]. This would indicate that O-GlcNAcylated YY1 will interact with AhR activation to increase the NAS/melatonin ratio, and thereby NAS trophic support for tumours [4]. As YY1 upregulates TGF-β induced proliferation and migration in breast cancer cells [82], and O-GlcNAcylation stabilises TGF-β pathways [83][84], O-GlcNAcylation will have multiple effects on factors that promote tumour proliferation and immune suppression.
By inhibiting Bmal1 [85][86], YY1 will also contribute to how circadian dysregulation induces immune suppression, in association with an increase in PD-1 in cytolytic cells [87]. As pineal melatonin requires Bmal1 to drive the conversion of pyruvate to acetyl-CoA by PDC, YY1 and its potentiation by O-GlcNAcylation will modulate mitochondrial metabolism and its interactions, via acetyl-CoA, with glycolysis, thereby increasing key factors in these cells that regulate immune suppression and cytolytic cell ‘exhaustion’. YY1, like AhR activation, will therefore inhibit pineal melatonin’s ‘resetting’ of immune cell metabolism over the circadian rhythm. YY1 can also promote cytolytic cell ‘exhaustion’ via COX2 [88], PD-L1 induction [89] and the epithelial-mesenchymal transition (EMT) [90], whilst adenosine effects include YY1 induction [91]. This would indicate a positive feedback loop, whereby the YY1 upregulation of TGF-β effects, including adenosine induction in MDSCs will lead to adenosine induction of YY1, with this feedback loop being positively regulated by O-GlcNAcylation.
As well as increasing TGF-β in cancer cells [90], YY1 also increases TrkB levels in subsets of cancer cells, as shown in the squamous cell carcinoma (SCC)-25 cell line [92]. As noted, TrkB levels are increased in breast and glioma CSC, where TrkB activation contributes to CSC survival, proliferation and treatment resistance [93]. This is another CSC survival cycle that is increased by the O-GlcNAcylation of YY1, which concurrently enhances immunosuppression via TGF-β1 effects, including via the induction of MDSC adenosine leading to A2Ar activation-driven ‘exhaustion’ in NK cells and CD8+ T cells [94]. O-GlcNAcylation and YY1 may therefore be important co-ordinators of tumour progression and immune suppression, driven by alterations in metabolism and the melatonergic pathway in cells of the tumour microenvironment.

4.3. O-GlcNAcylation: PFK1, HIF-1α, PGK1 and Sirtuins

Hypoxia is proposed to afford a growth advantage to tumours partly mediated by the O-GlcNAc potentiation of the glycolytic enzyme, phosphofructokinase 1 (PFK1) at S529, thereby driving the pentose phosphate pathway in the generation of NADPH and GSH, which protects tumours from raised ROS levels [95]. O-GlcNAcylation also protects HIF-1α from proteasomal degradation, thereby enhancing tumour aerobic glycolysis [96] and protecting tumours against apoptosis [97], including from decreased epigenetic regulation by HDAC1 [98],

4.4. O-GlcNAcylation: Sirtuins and Metabolism

As noted, SIRT1 regulates immune cells [52][53], as well as ageing-associated changes in acetyl-CoA and OXPHOS [55]. SIRT1 also acts via the deacetylation and activation of mitochondria-located SIRT3. SIRT3 enhances mitochondrial respiration and lowers ROS production, whilst upregulating acetyl-CoA, and therefore mitochondrial OXPHOS, TCA cycle and melatonergic pathway [99]. SIRT3 directly interacts with PDC to increase its enzymatic activity, and therefore potentiates the conversion of pyruvate to acetyl-CoA [100], whilst also increasing PDC via Bmal1 upregulation [101], and thereby optimising the circadian regulation of metabolism. Consequently, SIRT1 and SIRT3 are important regulators of tumour cell survival [102][103] and cell function in the tumour microenvironment [104][105], with SIRT1 overexpression in mesenchymal stem cells (MSC) enhancing NK cell attraction, thereby shifting MSC effects from potentiating to supressing tumour progression [106]. SIRT1 effects are cell-dependent, allowing SIRT1 and SIRT3 to have differential effects in the cells of the tumour microenvironment [104]. O-GlcNAcylation of SIRT1 lowers SIRT1 levels and activity in an AMPK-dependent manner, with O-GlcNAcylated SIRT1 inhibiting the proteasomal degradation of oncogenic transcription factors [107] and SIRT3 activity, thereby lowering SIRT1- and SIRT3-driven PDC disinhibition, OXPHOS, TCA cycle, ATP and acetyl-CoA availability as well as lowering SOD2 and melatonergic pathway activation.
Whether the O-GlcNAcylation of SIRT1 is co-ordinated with the O-GlcNAcylation of YY1 and VDAC2, thereby enhancing YY1 transcription and VDAC2 protection against mitochondrial apoptosis, requires investigation. Clearly, any potentiation of YY1-induced AANAT, if coupled to AhR-induced CYP1B1 and the NAS activation of the BDNF receptor, TrkB, could allow co-ordinated O-GlcNAcylation to provide trophic support to tumours, whilst protecting mitochondria, limiting OXPHOS, maintaining HIF-1α and upregulating PFK1, PGK1 [108] and therefore glycolysis and the pentose phosphate pathway [96]. As c-MYC, including via the PI3K/Akt/mTOR/c-MYC pathway [109], is sufficient to upregulate O-GlcNAc and OGT in tumours, whilst mTORC1-induced c-MYC and its induction of LAT-1 are core aspects of glycolytic metabolism, changes driven by O-GlcNAcylation are integral aspects of the alterations in metabolism classically associated with tumours, namely glycolysis upregulation and the limited maintenance of OXPHOS. The differential effects of O-GlcNAcylation in tumours and NK cells may be a crucial aspect to the development of immune suppression amongst the cells of the tumour microenvironment. Shifts in these processes, coupled to sirtuin regulation, would not only underpin the tumour phenotype but would then alter the metabolism-driven tumour fluxes that influence metabolic responses in the cells of the tumour microenvironment. O-GlcNAcylation is therefore important to dynamic, intercellular aspects of metabolism, including via, but not limited to, sirtuin regulation.

4.5. O-GlcNAcylation: Protein Phosphatase (PP)2A, AhR, and mTORC1

Protein phosphatases (PP), especially PP2A, are long recognised as important regulators of the tumour microenvironment [110], including cytolytic cells, with PP2A inhibiting granzyme B and cytotoxicity in NK cells [111]. PP2A is also a powerful regulator of the AhR [112], with PP2A and mTORC1 being in a negative reciprocal interaction [113], indicating that PP2A will inhibit mTORC1-induced LAT1 and glycolysis, thereby driving ‘exhaustion’ in NK cells.
PP2A dephosphorylates and therefore activates ACC, thereby decreasing acetyl-CoA levels [114], indicating that PP2A may modulate the interactions of mitochondrial OXPHOS with the acetyl-CoA pathway driving glycolysis upregulation, as well as decreasing acetyl-CoA for the melatonergic pathway. As such, the negative reciprocal interactions of mTORC1 and PP2A in glycolytic cells may involve a PP2A-induced decrease in the acetylation of Raptor, thereby leading to the mislocalisation of mTORC1, a key aspect of ‘exhaustion’ in NK cells and CD8+ T cells. The interactions of miR-375 with PP2A may be important, as miR-375 disinhibits PP2A suppression from Cancerous Inhibitor of PP2A (CIP2A) [115], whilst miR-375 also suppresses 14-3-3ζ, and therefore prevents 14-3-3ζ from stabilising AANAT and initiating the melatonergic pathway [116][117]. Overall, PP2A decreases acetyl-CoA, the melatonergic pathway and the acetylated Raptor/mTORC1/glycolysis pathway, with PP2A levels and effects modulated by miR-375, in co-ordination with suppression of 14-3-3ζ and the melatonergic pathway.
PP2A can be O-GlcNAcylated, thereby regulating its function [118]. PPP2R2A is a major regulatory subunit of PP2A, with PPP2R2A promoting cancer cell survival and proliferation. The downregulation of PPP2R2A results in an elevation in the total levels of cellular O-GlcNAcylation, as shown in breast cancer cells [119]. This would suggest that any protection that the above would indicate as arising from decreasing PP2A, would be offset by the consequences of wider O-GlcNAcylation. This would indicate an array of intra- and intercellular options for the maintenance of immune suppression in the tumour microenvironment.

4.6. O-GlcNAcylation: RACK1 and NLRP3 Inflammasome

Ribosomal receptor for activated C-kinase 1 (RACK1) is associated with chemoresistance and tumour growth [120], with increased levels of RACK1 correlating with tumour progression and fatality [121]. RACK1 may act via a variety of processes in tumours, including upregulating the assembly and activity of the NLRP3 inflammasome [120][122], miRNAs patterning [123], and AhR regulation [124]. Being a ribosomal protein, RACK1 modulates how ribosomes spatiotemporally coordinate patterned gene expression, including local translation process [125] and centrosome regulation [126][127]. RACK1 stabilises PP2A [128], and PP2A-associated immune suppression [110]. RACK1 also induces immune suppression by increasing the M2/M1 macrophage ratio [129] and suppressing the numbers of CD4+, CD8+, and iNK T cells [130], as well as promoting the EMT [131]. As RACK1, in interaction with GSK3α, can regulate the circadian clock in mammalian cells [132], alterations in RACK1 levels and its interactions are likely to have wider circadian-driven immune-regulatory consequences. RACK1 therefore regulates many tumour associated pathways [133][134].
The O-GlcNAcylation of RACK1 increases its stability [135] and effects [120][136], including its association with PKCβ2, thereby enhancing eukaryotic translation initiation factor 4E phosphorylation and the translation of numerous, potent oncogenes [120]. RACK1 is a component of the NLRP3 inflammasome, increasing IL-1β and IL-18 levels [120][122]. Elevations in O-GlcNAcylation are associated with increased NLRP3 inflammasome and NF-κB signalling activity [135], with the NLRP3 inflammasome important to cancer progression and tumour microenvironment regulation [120], with effects at least partly regulated by the O-GlcNAcylation of RACK1.
RACK1 may also be regulated by YY1 [137], indicating wider interactions with factors known to regulate the tumour microenvironment, including the melatonergic pathway. The RACK1 upregulation of the NLRP3 inflammasome, IL-1β and IL-18 will induce the IDO/kynurenine/AhR pathway and therefore melatonergic pathway suppression. The O-GlcNAcylation of RACK1 may therefore modulate the melatonergic pathway in the tumour microenvironment via both YY1 and NLRP3. Although it is the effects of O-GlcNAcylated RACK1 on the NLRP3 inflammasome that are thought to underlie its regulation of tumours, tumour microenvironment and immune therapy response [138], the interactions of O-GlcNAcylated RACK1 on circadian, YY1, PP2A, acetyl-CoA and the melatonergic pathway may better integrate the effects of RACK1 with other tumour regulatory factors and processes, including metabolic.

4.7. O-GlcNAcylation: Mesenchymal Stem Cells (MSC)

MSC can upregulate tumour PD-L1 [139] and are important tumour microenvironment regulators [140]. MSC can self-renew, have a multidirectional differentiation potential, and efflux large quantities of exosomes, thereby potentially acting as a hub to integrate and influence signals across the tumour microenvironment [141]. MSC can release mitochondria, both directly and within extracellular vesicles, which can be taken up by other cells, which may be a treatment target [142]. MSC can also regulate the mitochondrial function of other cells [143]. MSC are regulated by circadian genes [144] and melatonin, with melatonin regulating OXPHOS [145], SIRT1/SOD2 [146] and exosome/vesicle content [147][148]. This would indicate that the circadian regulation of mitochondria by melatonin/SIRT1/SIRT3/Bmal1/PDC/OXPHOS pathway will modulate the phenotype of transferred mitochondria, with consequences for the functioning of cells uptaking such potentially distinct mitochondria ‘phenotypes’. It requires clarification as to whether increased VDAC2, and its O-GlcNAcylation, afford protection in the process of mitochondria transfer. The relevance of variations in MSC exosomes and mitochondria ‘phenotypes’ in tumours and other cells of the tumour microenvironment will be important to determine, including over the circadian rhythm [147], given the known immune regulatory effects of MSC exosomes [149].
Preclinical in vivo data on mitochondria transfer into rodent tumours show such transfer to significantly alter the tumour microenvironment, including by lowering oxidative stress, tumour size and enhancing immune cell infiltration [150]. Such data clearly indicate the importance of targeting metabolic processes in changing the tumour microenvironment. It will be important to clarify the impact of different mitochondria ‘phenotypes’, including as arising from alterations in the location and presence of the melatonergic pathway.
MSC are also important inducers of IDO, which is stably upregulated by the O-GlcNAcylation of signal transducer and activator of transcription 1 (STAT1) in these cells [151]. As IDO-induced kynurenine inhibits NK cells and CD8+ T cells via AhR activation [8], this is another route whereby O-GlcNAcylation in MSC, as well as in CSC [8], may modulate immune suppression in the tumour microenvironment. Interestingly, heightened O-GlcNAc in MSC is coupled to increased glycolysis [151], indicating that O-GlcNAcylation in MSC will modulate the interface between OXPHOS and glycolysis in these cells. The roles of alterations in acetyl-CoA and the melatonergic pathway in determining the MSC influence on the tumour microenvironment as well as exosomal content and mitochondria ‘phenotypes’ will be important to determine.

4.8. O-GlcNAcylation: Glycogen Synthase Kinase (GSK)3β and Cytolytic Cells

GSK3β inhibitors increase the cytotoxicity and maturation of NK cells and CD8+ T cells [152][153], coupled to PD-1 suppression [154]. GSK3β inhibition underpins the co-stimulatory effects of CD28 on CD8+ T cell cytotoxicity [155], whilst ligand activation of the NK cell activator receptor, NKG2D, is prevented by GSK3β [156]. CD28 co-stimulatory effects on CD8+ T cells increase mitochondria fusion, membrane potential and mitochondrial mass [157], highlighting the impact of GSK3β inhibition on mitochondrial metabolism in driving cytotoxicity, which is also evident from the increased acetyl-CoA and TCA cycle activity, as well as glycolysis, required for the initial activation of memory CD8+ T cells [158].
In contrast to NK cells, heightened O-GlcNAcylation enhances the functional response of CD8+ T cells [74][75], which may be mediated via the inhibitory effects of O-GlcNAcylation on GSK3β function [159]. As GSK3β inhibition also increased NK cells cytotoxicity, this would indicate that the differential effects of O-GlcNAcylation in NK cells and CD8+ T cells are not mediated via the O-GlcNAcylation, and inhibition, of GSK3β [160][161].
GSK3β is also intimately linked to the melatonergic pathway, with GSK3β inhibition attenuating IFNγ induction of IDO, as shown in dendritic cells [162], thereby decreasing kynurenine production for AhR activation and increasing serotonin availability for the melatonergic pathway. The O-GlcNAcylation of GSK3β may enhance more optimal pathway activity in cytolytic cells, including the melatonergic pathway. GSK3β inhibition prevents IFNγ-induced IDO [162], including in cancer cells [163], and dendritic cells [164]. Such inhibition involves suppression of the Janus-activated kinase (JAK)1/PKCδ/STAT1 pathway, which is also inhibited by green tea’s epigallocatechin gallate (EGCG) [163] and curcumin [164], as well as other GSK3β inhibitors [162]. GSK3β inhibition, including by O-GlcNAcylation, will therefore modulate both cancer cells and cytolytic cells.
GSK3β inhibition has reciprocal positive interactions with melatonin, with melatonin increasing the PI3K/Akt and ser9 phosphorylation and inhibition of GSK3β and GSK3β inhibition suppressing IDO [162]. However, a STAT1 binding site is present in the AANAT promotor [165], allowing STAT1 activation of IDO by IFNγ to induce the melatonergic pathway and melatonin release. It is likely that the concurrent release of melatonin would negatively feedback on the IFNγ/GSK3β/JAK1/PKCδ/STAT1/IDO, although AhR/CYP1B1 via the backward conversion of melatonin to NAS would have contrasting effects via TrkB activation. Clearly, a number of factors and interacting processes have evolved to regulate mitochondria metabolism and the melatonergic pathway, arising from their significant influence on cellular and intercellular functions, including many of the key processes classically associated with CSC proliferation and immunosuppression in the tumour microenvironment.

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