Table 3 The changes in immune cells within the tumor immune microenvironment influenced by the nervous system
From: Cancer-nervous system crosstalk: from biological mechanism to therapeutic opportunities
Immune cell types | Mechanism of action of the nervous system | Changes in immune cells | Effects on tumors | Key molecule |
|---|---|---|---|---|
Tumor-Associated Macrophages (TAMs) [141] | Activate ADRB2 on tams [143] | Upregulate immunosuppressive molecules, pro-angiogenic VEGF [144], suppress pro-inflammatory cytokines | Impaire antitumor immunity, drive tumor progression [145] | IL-10↑, ARG1↑, VEGF↑, TNFα↓, IL-1β↓, IL-12↓ |
Activate Schwann cells, upregulate GFAP | Activate Schwann cells, polarize into M2 tumor-promoting phenotypes, form a TAM-Schwann cell positive feedback loop | Accelerate tumor metastasis [146] | GFAP↑ | |
Secrete NGF, activate the TrkA receptor | Trigger PI3K/AKT pathway, promote mTOR activation, increase VEGF and IL-6 | Enhance angiogenesis and tumor cell survival [161] | VEGF↑, IL-6↑ | |
Secrete GDNF, activate the RET tyrosine kinase receptor | Regulate tumor cell metabolic reprogramming, cytoskeletal dynamics, and microenvironmental adaptation | Promote tumor cells’ migration enhances perineural invasion capabilities [162] | GDNF↑ | |
Regulatory T Cells (Tregs) | Activate the camp/PKA pathway in Tregs, promote their migration into the tumor microenvironment | Suppress T-cell proliferation, downregulate cyclin D/E, upregulate p21/p27 | Suppress the antitumor immune response, enhance their own proliferation, reinforce immunosuppression, facilitate tumor immune evasion [151] | TGF-β↑, cell cycle proteins↓, cell cycle inhibitors↑ |
Activate the cAMP/PKA pathway in Tregs, promote their migration into the tumor microenvironment | Activating Foxp3, drive naïve CD4+ T-cell differentiation into immunosuppressive iTregs | Suppress the antitumor immune response, enhance their own proliferation, reinforce immunosuppression, facilitate tumor immune evasion [151] | TGF-β↑, Foxp3↑ | |
Activate the cAMP/PKA pathway in Tregs, promote their migration into the tumor microenvironment | Amplify by inducing IL-10, IL-35, and TGF-β secretion, form a self-reinforcing immunosuppressive loop | Suppress the antitumor immune response, enhance their own proliferation, reinforce immunosuppression, facilitate tumor immune evasion [151] | IL-10↑, IL-35 ↑, TGF-β↑ | |
Activate the cAMP/PKA pathway in Tregs, promote their migration into the tumor microenvironment | Bind CD80/CD86 on APCs, recruite SHP2 phosphatase, inhibit TCR signaling and block T-cell activation, reinforce immune suppression | Suppress the antitumor immune response, enhance proliferation, reinforce immunosuppression, facilitate tumor immune evasion [151] | SHP2 phosphatase↑ | |
Release NE, activate the β2-adrenergic receptor (β2-AR) | Trigger the camp-PKA signaling pathway, promote the secretion of IL-10 and TGF-β | Inhibit effector T cell activity, suppress anti-tumor immune responses [163] | IL-10↑, TGF-β secretion↑ | |
Neutrophils | Undergo enhanced production and modification, increase SP1 levels, facilitate neutrophil activation, secrete IL-1β | Activate MMP/ADAM proteases, release EGFR ligands, trigger EGFR-PI3K/AKT signaling [155], inhibit GSK-3β, stabilize EMT transcription factor, downregulate E-cadherin, upregulate vimentin, enhance cell motility | Enable superior adaptation to metastatic microenvironments, potentiate the metastatic capacity of cancer cells [157] | IL-1β↑, EGFR↑ |
Undergo enhanced production and modification, increase SP1 levels, facilitate neutrophil activation, secrete IL-1β | Bind to IL-1R, activate the MEK/ERK pathway [156], induce the expression of mesenchymal genes, enhance cell migration and invasion capabilities | Enable superior adaptation to metastatic microenvironments, potentiate the metastatic capacity of cancer cells [157] | IL-1β↑ | |
Secrete SPP1, release catecholamines by sympathetic nerves, enhance CXCL1 secretion, CXCL1 binds to the CXCR2 receptor | SPP1 binds to neutrophil surface receptor, activate the ERK pathway, promote NET formation; nets capture circulating tumor cells, release inflammatory mediators | Promote tumor cell survival and invasion [164] | SPP1↑, inflammatory mediators↑ | |
Natural Killer (NK) Cells | Release CGRP, bind to the CGRP receptors RAMP1 and CALCRL, activate AC, elevate intracellular camp levels, stimulate PKA [158] | Phosphorylate the transcription factor CREB, suppress IL-15 [159] | Drive tumor progression, exacerbate cancer-related pain, promote PDAC aggressiveness and pain hypersensitivity [160] | CGRP↑, IL-15↓ |
Release CGRP, bind to the CGRP receptors RAMP1 and CALCRL, activate AC, elevate intracellular camp levels, stimulate PKA [158] | Secret NGF, bind to the TrkA receptor, enhance CGRP release, establish a self-reinforcing feedback loop | Drive tumor progression, exacerbate cancer-related pain, promote PDAC aggressiveness and pain hypersensitivity [160] | CGRP↑ | |
Induce tumor cells or antigen-presenting cells to express PD-L1 | Bind to the PD-1 receptor, activate downstream inhibitory signaling pathways, suppress the PI3K/AKT/mTOR pathway, reduce the synthesis and release of cytotoxic granules | Suppres anti-tumor immunity [165] | PD-L1↑, cytotoxic granules↓ |