Hypoxia-Regulated Tumor-Derived Exosomes and Tumor Progression: A Focus on Immune Evasion
Abstract
:1. Background
2. Overview of Hypoxic and Tumor-Derived Exosomal Effects on Tumor Progression
2.1. Angiogenesis
2.2. Metastasis and Pre-Metastasis
2.3. EMT
2.4. Autophagy
2.5. Cell Survival and Proliferation
2.6. Therapy Resistance
2.7. Immune Evasion
3. Hypoxia-Inducible Factor (HIF)
4. Hypoxia and Tumor-Derived Exosomal Components
4.1. Hypoxia and Tumor-Derived Exosomal Protein
4.2. Hypoxia and Tumor-Derived Exosomal RNAs
4.3. Hypoxia and Tumor-Derived Exosomal Lipids
5. Immune Cell Evasion
5.1. Macrophages
5.2. Monocytes
5.3. Natural Killer (NK) Cells
5.4. T Cells
5.5. γδ. T lymphocytes
5.6. Myeloid-Derived Suppressor Cells (MDSCs)
5.7. Dendritic Cells
5.8. B Cells
5.9. Mast Cells
5.10. Regulatory T Cells
6. Escape of Immunogenic Cell Death via DAMPs
7. Escape from Immune Surveillance via Surface Recognition Molecules
7.1. PD-1/PD-L1
7.2. CD73/CD39
7.3. CD38
7.4. CD47
7.5. Other Surface Recognition Molecules
8. Escape from Immune Surveillance via Antitumor-Suppressive Molecules
8.1. TGF-β
8.2. IL-10
8.3. PGE2
8.4. VEGF
8.5. Others
9. Conclusions and Perspective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Exosomal Component | Tumor Type/Model | Effects | Reference |
---|---|---|---|
Exosomal RNAs | |||
lncRNA-UCA1 | Bladder cancer | Promotes tumor growth and progression through EMT in vitro and in vivo lncRNA-UCA1 in the human serum serves as a possible biomarker | [18] |
circ-133 | Colorectal cancer | Promotes cancer metastasis by acting on the miR-133a/GEF-H1/RhoA axis | [36] |
miR-128-3p, miR-140-3p, miR-340-5p, miR-452-5p, miR-769-5p and miR-1304-p5, miR-340-5p | Esophageal squamous carcinoma | Upregulated expression of these exosomal miRNAs in hypoxic esophageal squamous carcinoma cells | [44] |
lncRNA-UCA1 | Ladder cancer | Promotes cell proliferation, migration, and invasion | [18] |
miR-301a | Glioma | Activates Wnt/β-catenin signaling and promotes radiation resistance by targeting TCEAL7 | [52] |
miR-135b | Multiple myeloma | Enhances angiogenesis by targeting factor-inhibiting HIF-1 | [84] |
Exosomal proteins | |||
Cell migration-inducing and hyaluronan-binding protein (CEMIP) | Brain cancer | Increases pro-inflammatory cytokines Ptgs2, Tnf, and CCL/CXCL, which promote brain vascular remodeling and metastasis | [85] |
Integrin β3 | Lung Cancer | Mediates a brain-tropic metastasis pattern and may serve as a novel prognostic biomarker for brain metastasis | [75] |
Complement factor H (CFH) | Hepatocellular carcinoma | Promotes tumor cell growth, migration, invasiveness, and liver tumor formation in mice | [48] |
VEGF | TME | Its overexpression along with the activation of VEGFR induces immune-suppressive | [23] |
Wnt5b | Pancreatic cancer | Promotes cancer cell migration and proliferation | [76] |
Exosomal lipids | |||
Triglycerides | Prostate cancer | The activation of lipogenesis-related enzymes and signaling molecules causes increased accumulation of triglycerides in exosomes | [83] |
Phosphatidylserine | TME | Externalization of phosphatidylserine from the inner to the outer membrane leaflet of cells and exosomes provides strong immune-suppressive signals | [23] |
Phosphatidylserine | - | A critical molecule in the exosomal uptake by HUVECs. | [81] |
Immune Cell | Mechanism Involved | Effects Observed | Reference |
---|---|---|---|
Macrophage | The transfer of let-7a miRNA resulted in the suppression of the insulin-Akt-mTOR signaling pathway | Improved macrophage recruitment and M2-like polarization in vitro and in vivo Increased expression of immunomodulators, such as CSF-1, CCL2, FTH, FTL, and TGFβ | [24] |
Macrophage | miR-301a-3p activates the PTEN/PI3Kγ signaling pathway | Hypoxic exosomal miR-301a-3p induces M2 polarization of macrophages Hypoxic exosomes enhance malignant behaviors of pancreatic cancer cells | [78] |
Macrophage | Macrophage expression of HIF-1α | Tumor-associated macrophages suppress tumor-infiltrating T cells | [146] |
Macrophage | Exosomal miRNAs are induced by hypoxia vian HIFs | Tumor-associated macrophages educated by hypoxic exosomes derived from cancer cells promote tumor proliferation and migration in a feedback loop. | [147] |
Macrophages Monocytes | MyD88-p38-STAT3 signaling The tumor cell-released TLR4-mediated autophagosomes-PD-L1 axis | Tumor cell-released autophagosomes-induced macrophage polarization into M2-like phenotype characterized by the expression of PD-L1 and IL-10 M2-like phenotype with increased expression of PD-L1, CD163, and IL-10, but decreased HLA-DR with T cell-suppressive function | [93] |
Monocyte | Exosomal delivering of miRNA-21 | Monocyte transformation to M2-like macrophages via miRNA-21, with increased expression of IL-10 and CD206 | [98] |
T-cells | miR-24-3p targets FGF11 to inhibit T-cell function | Hypoxia increases cellular and exosomal miR-24-3p levels and enhances the inhibitory effect on T-cell proliferation and differentiation | [57] |
T cells | Targeted depletion or elimination of hypoxia in tumors | Increased T cells infiltration into hypoxic zones and downregulation of MDSCs | [105] |
Γδ T-cell (lymphocyte) | Hypoxic exosomes regulate MDSC function in a miR-21/PTEN/ PD-L1-axis-dependent manner | There is an enhanced suppressive effect of MDSCs on γδ T cells | [108] |
γδ T cells | Reduced calcium efflux and the expression of CD107a in γδT cells | Decreased antitumor cytotoxicity of γδT cells observed under hypoxia | [114] |
MDSC | Increased level of exosomal S100A9 vian HIF-1α-dependent mechanism | MDSCs enhance colorectal cancer cell stemness and growth | [119] |
MDSCs Regulatory B cells | Microvesicles transport membrane-bound PD-L1 from MDSCs to B cells | Suppressed CD8+ T-cell activation, and increased CD155, TGFβ, and IL10 | [135] |
DC | PD-1/PD-L1 pathway | DCs treated with tumor cells exosomes significantly increase PD-1+CD8+T cells | [130] |
DC | Hypoxia induces upregulation of microRNA 21 in DCs | Decreased expressions of CD80, CD86, and MHCII on DCs | [126] |
B cells | Hypoxia-induced IL-10 secretion via HMGB1 | Hypoxia significantly enhances the level of HMGB1 on tumor cell-released autophagosomes leading to the induction of IL-10-producing B cells that suppress CD4+ and CD8+ T cells | [134] |
B cells | IL-10-dependent manner Activation of the TLR2-MyD88-NF-κB signal pathway in B cells | B cells differentiate into IL-10-producing regulatory B cells with a distinct phenotype of CD1d(+) CD5(+), which could potently inhibit CD8(+) and CD4(+) T cell responses | [133] |
NK cells | Hypoxic tumor-derived microvesicles miR-23a and TGF-β1 | Transfer of TGF-β1 and miR-23a to NK cells, decreases NKG2D, thereby inhibiting NK cell function. | [100] |
Mast cells | CD40L-CD40 interaction | Promote PMN-MDSCs activity and T-cell inactivity to favor the suppression of antitumor activities and encourage tumor onset | [137] |
Mast cells | Increased expressions of HIF-1α, VEGF, and H1 | Increased tumor growth and angiogenesis. And decreased survival rate of the mice | [139] |
Mast cells | CCL5 dependent | Increased suppression of antitumor function and enhanced tumor progression | [141] |
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Shao, X.; Hua, S.; Feng, T.; Ocansey, D.K.W.; Yin, L. Hypoxia-Regulated Tumor-Derived Exosomes and Tumor Progression: A Focus on Immune Evasion. Int. J. Mol. Sci. 2022, 23, 11789. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911789
Shao X, Hua S, Feng T, Ocansey DKW, Yin L. Hypoxia-Regulated Tumor-Derived Exosomes and Tumor Progression: A Focus on Immune Evasion. International Journal of Molecular Sciences. 2022; 23(19):11789. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911789
Chicago/Turabian StyleShao, Xuejun, Shenghao Hua, Tao Feng, Dickson Kofi Wiredu Ocansey, and Lei Yin. 2022. "Hypoxia-Regulated Tumor-Derived Exosomes and Tumor Progression: A Focus on Immune Evasion" International Journal of Molecular Sciences 23, no. 19: 11789. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911789