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Review
. 2024 Jul 25:15:1353787.
doi: 10.3389/fimmu.2024.1353787. eCollection 2024.

Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy

Affiliations
Review

Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy

Andrea Nicolini et al. Front Immunol. .

Abstract

Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.

Keywords: colorectal cancer; immunotherapy; metabolic reprogramming; tumor immune escape; tumor immune microenvironment.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Main mechanisms of metabolic tumor cell reprogramming and tumor immune suppression in TIME. m.r.; metabolism reprogramming; TIME: tumor immune microenvironment; ASTC2 = SLC1A5: solute carrier family 1 member A5; GLS1: glutaminase 1; MCT4: monocarboxylate transporter 4; TCA: tricarboxylic acid; LDH: lactate dehydrogenase; mCAIX: membrane carbonic anhydrase; Tregs: T regulatory cells; MDSCs: myeloid-derived suppressor cells; HIF-1α: hypoxia inducible factor 1 alpha; ATP: adenosine triphosphate; ROS: reactive oxygen species; PI3K: phosphoinositide-3 kinase; Akt: protein kinase B; mTOR: mammalian target of rapamycin; MAPK: mitogen-activated protein kinase; M2: macrophage type 2; ⇧ increase; ⇩ decrease.
Figure 2
Figure 2
Main mechanisms of tumor immune escape in tumor immune microenvironment (TIME) through metabolic reprogramming in T cells. LDH: lactate dehydrogenase; INFγ: interferon gamma; HIF-1α: hypoxia inducible factor 1 alpha; OXPHOS: oxidative phosphorylation; Treg: T regulatory cell; FABP5: fatty acid binding protein 5; AMPK: AMP-activated protein kinase; TCA: tricarboxylic acid; FA: fatty acid; FAO: fatty acid oxydation; MCT1: monocarboxydate transporter1; PD1: programmed death protein 1; pDCs: plasmacytoid dendritic cells; STING: stimulator of interferon genes; Th: T helper; DAMPs: death/damage-associated molecular proteins; LPO: lipid peroxydase; IL: interleukin; p38MAPK: p38 mitogen-activated protein kinase; ⇧ increase; ⇩ decrease; ⟞ inhibited.
Figure 3
Figure 3
Main mechanisms of immune escape in tumor immune microenvironment (TIME) through metabolic reprogramming in macrophages, neutrophils and myeloid derived suppressor cells. (A) M1, M2: macrophage type 1 and type 2 phenotype; TGFβ: tumor growth factor beta; IL: interleukin; FAs: fatty acids; MCT1: monocarboxylic transporter 1; OXPHOS: oxidative phosphorylation; FAO: fatty acid oxidation; ROS: reactuve oxygen species; Tregs: T regulatory cells; IDO: indoleamine 2,3 dioxygenase; ARG: arginase; GTLY: glutaminolysis. (B) NETosis: neutrophils extracellular transactivation and release; TNFα: tumor necrosis factor alpha; ATP: adenosin triphosphate; CXCL: chemokine ligand; PPP: pentose phosphate pathway; P2X, P2Y: purinergic receptors; N2: neutrophil type 2; TANs: tumor-associated neutrophils; OXPHOS and ROS: see panel A. (C) MDSC: myeloid derived suppressor cell; HIF-1α: hypoxia inducible factor 1 alpha; CXCR: chemokine receptor; AMPK: 5’ adenosine monophosphate activated protein kinase; L-Glu: L-glutamine; CD36: cluster of differentiation 36; TCA: tricarboxylic acid; PGE2: prostaglandin E2; NK: natural killer; GM-CSF: granulocyte-macrophage colony stimulating factor; STAT-5: signal transducer and activator of transcription 5; FATP2: fatty acid transport protein 2; CXCL: see panel B; FAO: see panel A; ⇧ increase; ⇩ decrease.
Figure 4
Figure 4
Main mechanisms of immune escape in tumor immune microenvironment (TIME) through metabolic reprogramming in dendritic and natural killer cells. (A) DLN: draining lymph-nodes; TADC: tumor-associated dendritic cell; TIME: tumor immune microenvironment; AMPK: 5’ adenosine monophosphate-activated protein kinase; OXPHOS: oxidative phosphorylation; FAO: fatty acid oxidation; COX2: cyclooxygenase2; IDO: indoleamine pyrrole-2,3-dioxygenase; TGFβ: transforming growth factor beta; IL: interleukin; VEGF: vascular endothelial growth factor; MSR1: macrophages scavenger receptor 1; GCN2: general control non depressing 2; A2bR: adenosine A2B receptor; PGE2: prostaglandin E2; CCL5: chemokine (C-C motif) ligand 5; XCL1: chemokine (C motif) ligand 1. (B) NK: natural killer; EOMES: eomesodermin; ROS: reactive oxygen species; ILC1s: innate lymphoid cell group 1; i-ILC2s: inflammatory innate lymphoid cells group 2; n-ILC2s: natural innate lymphoid cells group 2; GM-CSF: granulocyte-macrophage colony stimulating factor; MDSC: myeloid derived suppressor cell; IL: interleukin; IL25R: interleukin 25 receptor; OXPHOS and FAO: see panel A; ⇧ increase; ⇩ decrease; —I inhibited.
Figure 5
Figure 5
High fat diet, aerobic glycolisis and main characteristics of metabolic reprogramming in CRC. TCA: tricarboxilic acid; ACSL: acyl-CoA synthetase; SCD: stearoyl-CoA desaturase; EMT: epithelial to mesenchymal transition; FAO: fatty acid oxydation; DHAP: dihydroxyacetone phosphate; G-6P: glucose 6 phosphate; F-6P: fructose 6 phosphate; F-1,6BP: fructose 1,6 biphophate; G-3P: glucose 3 phosphate: 3-PG: 3 phosphogliceric acid; PEP: phosphoenolpyruvate; PKM: pyruvate kinase muscle isoenzyme; LDH: lactate dehydrogenase; MCT: monocarboxylate transporter; 1-C: one carbon; SHMT: serine hydroxymethyltransferase; MTHFD1L: methylene tetrahydrofolate dehydrogenase 1-like; ASCT: alanine, serine, cysteine transporter; ATRiP: ATR interacting protein; KCY: colonic lysine homocysteinylation; ATR: ataxia-teleangectasia and RAD 3-related protein; HTL: homocysteine thiolactone: MARS: methionyl-tRNA synthetase; CHK1: cheek point kinase 1; HCY: homocysteilation; ⇧ increase; ⇩ decrease.
Figure 6
Figure 6
(A) Genetic and epigenetic regulation of glycolysis in CRC. EGFR: epidermal growth factor receptor; APC: adenomatous polyposis coli gene; PI3K: phosphoinositide-3-kinase; Akt: protein kinase B; mTOR: mammalian target of rapamycin; PTEN: phosphatase and tensin homolog; KRAS: kirsten and sarcoma virus gene; P53: tumor protein 53; GLUTs: glucose transporters; MCT: monocarboxylate transporter; HK2: hexokinase 2; F2,6BP: fructose 2,6 biphosphate; HIF1: hypoxia inducible factor 1; PKM: pyruvate kinase muscle isoenzyme; PDK1: piruvate dehydrogenase kinase 1; TCF: T cell factor; METTL3: methyl adenosine (m6A) transferase; LDHA/B: lactate dehydrogenase A/B. (B) Metabolic reprogramming and some main mechanisms of immune escape in the colorectal tumor immune microenvironment (TIME). TILs: tumor infiltrating lymphocytes; CRC: colorectal cancer; GPR81: G-protein coupled receptor 81; Ap2α: activating protein 2 alpha; Elk-1: ETS-like 1 protein; DC: dendritic cell; NFAT: nuclear factor of activated T cells; M2: macrophage phenotype 2; Treg: T regulatory cells; TAM: tumor-associated macrophage; ⇧ increase; ⇩ decrease; ⟞ inhibited.

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