Table 1.
Functional immune responses triggered by nucleotides and nucleosides actions in glioblastoma microenvironment.
| Main purinergic receptors | Immune outcome | Immune cell profile | Cytokine & chemokine profile | Ref | ||
|---|---|---|---|---|---|---|
| Immunostimulatory | ATP | P2X1 | Proinflammatory response | Chemotaxis of neutrophils; chemotaxis and phagocytosis of macrophages; release of chemokines and cytokines from eosinophils; T cell activation. | IL-2, IL-8, IL-12, TNF-α (increased) |
(57–61) |
| P2X4 | Proinflammatory response | Microglia activation and proliferation; macrophages stimulation and maturation; stimulation of dendritic cells; T cell activation. | IL-2, IL-12, TNF-α (increased) |
(54, 57, 59–62) | ||
| P2X5 | Adaptative immune response | T and B lymphocytes activation. | IL-2 (increased) |
(57, 60) | ||
| P2X7 |
Proinflammatory response
NLRP3 inflammasome activation |
Recruitment of macrophages and neutrophils; inhibition of the suppressive potential of Tregs. | IL-1β, IL-12, IL-18, IFN-γ, TNF-α, CCL-3, CXCL2 (increased) |
(54, 57, 60–65) | ||
| P2Y2 | Innate immune response | Chemotaxis of eosinophils, monocytes/macrophages, microglia, and dendritic cells; degranulation of neutrophils. | MCP-1, CCL2, IL-6, IL-8, IL-33 (increased) |
(57, 66) | ||
| Immunosuppressive | ADO | A2a | Immunosuppressive response | Macrophage differentiation into M2 phenotype; T cell anergy; increase differentiation and suppressive effect of Treg; upregulation of immune checkpoint receptors (e.g., PD-1, CTLA-4); reduction of NK cell cytotoxicity; inhibition of neutrophil and microglial chemotaxis; modulation of chemokines profile in neutrophils. | IL-10, VEGF, TGF-β (increased) IL-12, TNF-α, nitric oxide; IFN-γ (decreased) |
(57, 64, 67–70) |
| A2b | Anti-inflammatory response | Macrophage differentiation into M2 phenotype; reduction of monocyte differentiation to dendritic cell; MDSCs expansion; reduction of adherence and degranulation of neutrophils. | Arginase 1, IL-10, VEGF, IL-6; TGF-β (increased) IL-12, TNF-α (decreased) |
(57, 68, 70) |
ATP, adenosine 5′-triphosphate; ADO, adenosine; CCL3, C-C motif chemokine ligand 3; CXCL2, C-X-C motif ligand 2; CTLA-4, cytotoxic T-lymphocyte antigen 4; IFN-γ, interferon γ; IL-, interleukine; MCP-1, monocyte chemoattractant protein-1; MDSC, myeloid-derived suppressor cell; NK, natural killer; NLRP3, sensor molecule (NOD- LRR- and pyrin domain-containing protein 3); PD-1, programmed cell death 1; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor.