Int J Stem Cells.  2024 Aug;17(3):270-283. 10.15283/ijsc24060.

Glutathione Dynamics in the Tumor Microenvironment: A Potential Target of Cancer Stem Cells and T Cells

• Park Y
• Jeong EM

• KMID: 2558605
• DOI: http://doi.org/10.15283/ijsc24060

Abstract

Glutathione (GSH), the main cellular antioxidant, dynamically influences tumor growth, metastasis, and resistance to therapy in the tumor microenvironment (TME), which comprises cancer cells, immune cells, stromal cells, and non-cellular components, including the extracellular matrix, metabolites, hypoxia, and acidity. Cancer stem cells (CSCs) and T cells are minor but significant cell subsets of the TME. GSH dynamics influences the fate of CSCs and T cells. Here, we explored GSH dynamics in CSCs and T cells within the TME, as well as therapeutic approaches that could target these dynamics.

Keyword

Glutathione dynamics; Cancer stem cells; T cells; Tumor microenvironment

Figure

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  Fig. 1 Glutathione (GSH) dynamics of cancer stem cells (CSCs) in tumor microenvironment (TME). In the TME, the CSCs dynamically modulate their GSH regeneration capacity for survival. (A) Cytosolic nicotinamide adenine dinucleotide phosphate (NADPH) was mainly supplied via the pentose phosphate pathway (PPP). Under oxidative stress, glyceraldehyde 3-phosphate dehydrogenase is inactivated via the oxidation of cysteine thiol residues at its active site, and glucose 6-phosphate dehydrogenase (G6PD) is activated by ataxia-telangiectasia mutated serine/threonine kinase (ATM), leading to the potentiation of PPP. (B) Cytosolic GSH synthesized from glutamate, cysteine, and glycine can scavenge reactive oxygen species (ROS) via glutathione peroxidase (GPX) and can be regenerated by glutathione reductase (GSR) with NADPH, leading to the generation of a redox buffering cycle. (C) In the mitochondrial matrix, mitochondrial ROS (mtROS) are produced via superoxide dismutase 2 (SOD2) acetylation by GCN5L1 and can be removed by mitochondrial GSH and NADPH pools. (D) Plasma membrane is protected by GPX4 from lipid peroxidation and ferroptosis. GSH and oleic acid present in the lymphatic vessels inhibit CSCs’ ferroptosis. (E) Cytosolic NADPH is produced by isocitrate dehydrogenase 1 (IDH1). (F) Mitochondrial NADPH is supplied by IDH2 which transforms isocitrate to α-ketoglutarate (α-KG) as a reaction of the citric acid cycle. α-KG is also produced by mitochondrial glutaminase (GLS) and the glutamine transamidase reaction. (G, H) Cytosolic NADPH is produced by malic enzyme 1 (ME1, G) and the folate pathway (H). (I) CSCs derived-DKK1 inhibits Wnt signaling and increases SLC7A11 expression, leading to the inhibition of ferroptosis. Cys2: cysteine, DHA: dehydroascorbate, F1,6BP: fructose 1,6-bisphosphate, G3P: glyceraldehyde 3-phosphate, G6P: glucose 6-phosphate, GSSG: glutathione disulfide, OAA: oxaloa-cetate, THF: tetrahydrofolate.

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  Fig. 2 Transcriptional factors (TFs) regulating glutathione (GSH) dynamics in cancer stem cells. TFs and their targeting genes are involved in GSH dynamics. ROS: reactive oxygen species, NADPH: nicotinamide adenine dinucleotide phosphate.

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  Fig. 3 Regulation of cancer stem cells (CSCs) by glutathione (GSH) dynamics during tumorigenesis stages. (A) According to tumorigenesis stages, reactive oxygen species (ROS) differently regulate the expression levels of GSH-related and metastatic genes in CSCs. (B, C) CSCs can be classified into mesenchymal-type cells (M-CSCs) and epithelial-type cells (E-CSCs) differentiated by EMT and MET, respectively. Both processes are critically regulated by redox signaling (B). M-CSCs are dependent on glycolysis and superoxide dismutase acetylation of lysine 68 (SOD2K68Ac)-mediated mitochondrial ROS (mtROS). E-CSCs are dependent on oxidative phosphorylation (OXPHOS) and basal ROS. E-CSCs are more dependent on GSH levels compared to M-CSCs for their survival (C). NOX: NADPH (nicotinamide adenine dinucleotide phosphate) oxidase, TGF-β: transforming growth factor-β, GFs: growth factors, 2DG: 2-deoxyglucose, EMT: epithelial-mesenchymal transition, MET: mesenchymal-epithelial transition.

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  Fig. 4 Mechanistic insights into the network between T cell and stem cells. (A) Background information on how CD4＋ T helper subsets are generated. (B) Each type of CD4＋ T helper subset plays a distinct role in the fate of intestinal stem cells. Effector cytokines (interferon [IFN]-γ, interleukin [IL]-4, IL-17A) from T helper 1 (Th1), Th2, and Th17 mediated the differentiation of Lgr5＋ intestinal stem cells, which leads to the generation of goblet cells, tuft cells, and Paneth cells. On the other hand, IL-10 from Tregs induce self-renewal of intestinal stem cells. (C) IL-17 from Tregs promotes the stemness of colorectal cancer by upregulating CD44, CD133, and EpCAM on cancer stem cells (CSCs). Tregs-derived prostaglandin E2 (PGE2) activates NF-κB, expanding CSCs. In hypoxic conditions, transforming growth factor-β (TGF-β) from Tregs induces vascular endothelial growth factor (VEGF), which enhances angiogenesis to nourish CSCs. (D) CSCs secrete IL-23, IL-6, IL-8, IL-1β, which polarize Th17 differentiation. Then, IL-17 and IL-22 from Th17 help, in part, CSC survival. CSCs induce the differentiation and recruitment of Tregs. TGF-β and IDO 1 from CSCs act on naïve CD4＋ T cells to differentiate into Tregs. CCL2 and CCL5 from CSCs recruit Treg in CCR4 and CCR5-dependent manners. Moreover, CSCs not only upregulate immune checkpoint molecules such as PDL1 and CTLA4 but also reduce MHC I expression, which hinders anti-tumor T cell responses.

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  Fig. 5 The network of redox signaling for determining the fate of T cells. (A) Superoxide radicals are generated at various subcellular spaces and undergo enzymatic conversion into H2O2 by superoxide dismutase (SOD). Glutathione (GSH) reduces H2O2 levels by converting it into water. Upon T cell receptor (TCR) stimulation, NOX becomes activated to generate H2O2. H2O2 selectively oxidizes thiol groups on the surface or cytosol of T cells, modulating diverse cellular processes, including DNA synthesis, epigenetic regulation and post-translational modifications. Cysteine from antigen-presenting cells (APCs) is resorbed by T cells and assimilated into an enzymatic process generating GSH. GSH preserves the reduced status of thiol on the surface of the cell, mitigating H2O2 effects. Thioredoxin (TRX) synthesized by T cells, APCs, and Tregs contribute to maintaining the thiol group on the cell surface. (B) Antigen-stimulated T cells express active NOX that generates reactive oxygen species (ROS) in the cytosol. ROS induce conformational changes in Keap1, which leads to Nrf2 translocation into the nucleus. Nrf2 binds to antioxidant response elements (AREs) in the promoter region of glutamate-cysteine ligase catalytic subunit (GCLC) catalyzing GSH synthesis. This figure depicts how NOX, Keap1, and GCLC knock-out affect the function of T cells in various disease conditions. (C) ROS stabilizes SENP3 that drives deSUMOylation of BACH2, which potentiates Tregs expansion through enhancing Foxp3 expression. Moreover, ROS mediates H3K27 acetylation at Foxp3 promoter, which accelerates the transcription of Foxp3 gene. Conversely, mitochondrial ROS accumulation in autoimmune conditions causes DNA damage in Tregs, causing the death of Tregs. NOX: NADPH (nicotinamide adenine dinucleotide phosphate) oxidase.

Reference

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