Mechanisms of cell communication involved in tumour establishment, invasion and immune escape in glioma TME. (IMAGE)
Caption
(A) Resident microglia are polarized toward a pro-tumorigenic state, often mediated by glioma-derived factors like Versican. These cells facilitate tumor progression by MMP14 and STI1, SPP1, and EGF. They also contribute to the immunosuppressive niche through the expression of PD-L1 and TGF-β. (B) Circulating monocytes are recruited in glioma via the CCL2/CCR2 and CSF1/CSF1R signaling axes. Once infiltrated, they differentiate into tumor-associated macrophages. These cells exhibit a functional spectrum: while some maintain pro-inflammatory roles (secreting IL-1β, IL-27, and TNF), the majority adopt an anti-inflammatory and immunosuppressive phenotype characterized by high expression of PD-L1, TGF-β, IL-10, and ARG1. Tumor-associated macrophages also drive angiogenesis through VEGF/EGF and remodel ECM via MMP2. (C) Neutrophils are recruited to glioma via IL-8 signaling. Neutrophils promote the further infiltration of themselves and monocytes to glioma TME. They also promote an immunosuppressive niche by expressing ARG1. Specially, "hybrid" dendritic-like neutrophils may possess anti-tumoral potential by priming T-cell cytotoxicity and memory responses. (D) MDSCs are recruited from the circulation via CCL2 and stromal cell-derived factor 1α (SDF-1α). MDSCs are potent inhibitors of T cell activity, utilizing ARG1, inducible nitric oxide synthase (iNOS), PD-L1, and TGF-β to stifle the adaptive immune response. (E) The glioma TME actively impairs the "sentinel" function of DCs. Glioma-derived factors, including VEGF, IL-6, and IL-10, inhibit the maturation and antigen-presentation capabilities of DCs, preventing the effective priming of anti-tumor T cells. (F) The adaptive immune arm is characterized by a "highly immunosuppressive state." T cells undergo exhaustion or apoptosis following interactions between PD-1 and PD-L1. The upregulation of TGF-β and IDO1 further suppresses T cell activity. (G) Glioma cells form functional synapses with neurons, hijacking neurotransmitters such as Glutamate and GABA to drive tumor progression. Neurotrophic factors, including NLGN3, BDNF, IGF1, and SEMA4F, provide essential growth-promoting signals to the tumor cells. (H) Reactive astrocytes communicate with glioma cells through gap junctions. Glioma cells also communicate with astrocytes through IL-11/IL11RA and ANXA1/FRR1 axes to suppress T cell immunity. (I) Endothelial cell-derived VEGF and FGF stimulate angiogenesis and promote tumor growth. The vasculature is often structurally compromised, leading to blood-brain barrier (BBB) disruption. This facilitates the infiltration of peripheral immune cells but also results in poor drug delivery. (J) Lymphatic endothelial cells interact with tumor cells via the CCL21/CCR7 axis to promote tumor growth. ANXA1, annexin A1; FRR1, fragile site-related protein 1; ARG1, arginase 1; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; CCL2, C-C motif chemokine ligand 2; CCL21, C-C motif chemokine ligand 21; CCR2, C-C motif chemokine receptor 2; CCR7, C-C motif chemokine receptor 7; CSF1, colony-stimulating factor 1; CSF1R, colony-stimulating factor 1 receptor; CXCR4, C-X-C motif chemokine receptor 4; ECM, extracellular matrix; EGF, epidermal growth factor; FGF, fibroblast growth factor; GABA, gamma-aminobutyric acid; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; IDO1, indoleamine 2,3-dioxygenase 1; IGF1, insulin-like growth factor 1; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; IL-11, interleukin-11; IL-27, interleukin-27; IL11RA, interleukin-11 receptor subunit α; iNOS, inducible nitric oxide synthase; MDSCs, myeloid-derived suppressor cells; MMP2, Matrix metalloproteinase-2; MMP14, Matrix metalloproteinase-14; NF-κB, nuclear factor kappa B; NLGN3, neuroligin-3; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; p-STAT, phosphorylated signal transducer and activator of transcription; SDF-1α, stromal cell-derived factor 1 α; SEMA4F, semaphorin 4F; SPP1, secreted phosphoprotein 1; STI1, stress-inducible protein 1; TGF-β, transforming growth factor beta; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
Credit
Chinese Medical Journal
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