Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment
Abstract
:1. Introduction
1.1. Extracellular Vesicles
1.2. The Tumor Microenvironment
1.3. EVs and the Tumor Immune Microenvironment
2. EVs and Tumor Immune Suppression
2.1. EVs and Tumor Immune Suppression: Role of T and B Cells
2.2. EVs and Tumor Immune Suppression: Role of Tregs
2.3. EVs and Tumor Immune Suppression: Role of Natural Killer Cells
2.4. EVs and Tumor Immune Suppression: Role of MDSCs
2.5. EVs and Tumor Immune Suppression: Role of Antigen Presenting Cells
2.6. EVs and Tumor Immune Suppression: Role of Monocytes and Macrophages
3. Immune Cells-Derived EVs
4. EV-Mediated Immune Activation
5. Translational Applications: Targeting EV-Mediated Tumor Immune Suppression
6. Limitations and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
A | |
AML | acute myeloid leukaemia |
APCs | antigen presenting cells |
ARG1 | arginase-1 |
B | |
BAG6 | large proline-rich protein BAG6 |
C | |
CCL2 | C-C motif chemokine ligand 2 |
CCRs | chemokine receptors |
CLL | chronic lymphocytic leukemia |
CRC | colorectal cancer |
D | |
DAMPs | damage-associated molecular patterns |
DC | dendritic cells |
E | |
eTreg | effector Treg |
EGFR | epidermal growth factor receptor |
EMT | epithelial mesenchymal transition |
EOC | epithelial ovarian cancer |
ECM | extracellular matrix |
EVs | Extracellular Vesicles |
F | |
FAS-L | tumor necrosis factor ligand superfamily, member 6 |
FDA | Food and Drug Administration |
G | |
LGALS9 | galectin 9 |
GBM | glioblastoma multiforme |
gp100 | glycoprotein 100 |
H | |
HNSCC | head and neck squamous |
HDGF | hepatoma-derived growth factor |
HSP70 | heat shock protein 70 |
HA | hyaluronan |
HA | hyaluronic acid |
I | |
iDC | Immature DCs |
ICP | immune checkpoint proteins |
ICD | immunogenic cell death |
IFN-β | interferon-β |
L | |
LGALS9 | galectin 9 |
LPS | lipopolysaccharide |
lnc | long non-coding |
LNs | lymph nodes |
CD107a/LAMP1 | lysosomal-associated membrane protein 1 |
M | |
MEKK2 | MEK kinase 2 |
MART1 | melanoma-associated antigen 3-MAGE-A3 |
MIF | macrophage migration inhibitory factor |
MUC1 | mucin-1 |
MM | multiple myeloma |
MDSCs | Myeloid-derived suppressor cells |
N | |
NK | natural killer |
NKG2DL | NKG2D ligand |
NPM1 | nucleophosmin |
P | |
PDAC | pancreatic ductal adenocarcinoma |
PDCD4 | programmed cell death factor 4 |
PD1 | programmed death 1 |
PD-L1 | programmed death ligand 1 |
PGE2 | prostaglandin E2 |
PLP2 | proteolipid protein 2 |
R | |
RFXAP | regulatory factor X-associated protein |
Tregs | regulatory T cells |
S | |
SIRPalpha | signal regulatory protein alpha |
SCLC | small cell lung cancer |
sNMase | neutral sphingomyelinase |
nSMase | sphingomyelinase |
SPHK1 | sphingosine kinase-1 |
SPHK1 | sphingosine kinase 1 |
SCC | squamous cell carcinoma |
T | |
TCR | T-cell receptor |
TERF1 | telomeric repeat binding factor 1 |
TβRII | TGF-β type II receptor |
TLR4 | Toll-like receptor 4 |
TGF-β | transforming growth factor β |
SMAD3 | transforming growth factor-beta signaling protein 3 |
TAAs | tumor associated antigens |
TME | Tumor Microenvironment |
TNF | tumor necrosis factor |
TRAIL | tumor necrosis factor (TNF)-related apoptosis-inducing ligand |
TAMs | tumor-associated macrophages |
TEVs | tumor-derived EVs |
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Cancer Type (EV-Source) | Functional Molecules | Recipient/Target Cells | Functional Effect in Recipient Cells | References |
---|---|---|---|---|
Small cell lung cancer | PD-L1 | T cells | Inhibition of T cell activation | [53] |
Ovarian cancer | ARG1 | T cells | Suppression of T cells proliferation | [48] |
Ovarian cancer | SPHK1 | T cells | Promotion of T cell exhaustion | [54] |
Breast cancer | TβRII | T cells | CD8+ T cell exhaustion via SMAD3 and TCF1 | [55] |
Melanoma | miR-3187-3p, miR-498, miR-122, miR149, miR-181a/b | T cells | Inhibition of T cell activation | [56] |
Leukemia | miR-19a-3p | T cells | Suppression of T cells immune function | [57] |
Melanoma and squamous cell carcinoma of head and neck | FasL | T cells | Apoptosis of CD8+ T cells and Treg expansion | [58] |
Head and neck cancer | PD-L1 | CD8+ T cells | Decreased CD8+ T cell activation | [59] |
Glioblastoma cancer | PD-L1 | T cells | Suppressed T cell activation and proliferation | [47] |
Breast cancer | PD-L1 | T cells | Impaired activation and cancer killing potential of T cells | [60] |
Prostate and melanoma | PD-L1 | CD8+ T cells | Suppressed T cell activity | [61] |
Non small cell lung cancer | PD-L1 | CD8+ T cells | Immunosuppressive properties | [62] |
Melanoma | PD-L1 | T cells | Suppressed T cell functions | [52,63] |
Gastric cancer | PD-L1 | T cells | Apoptosis of T cells; reduced activation of peripheral blood mononuclear cells | [64] |
Hepatocellular carcinoma | 14-3-3ζ | T cells | Immunosuppressive phenotype | [65] |
Ovarian cancer | Ganglioside GD3 | T cells | Decreased T cell activation | [66] |
Ovarian cancer | T cells | Suppressed T cell functions | [67] | |
Melanoma | CD8+ T cells and NK cells | Enhanced apoptosis and suppressed proliferation and activation of CD8+ T cells; decreased NKG2D in NK cells | [68] | |
Head and neck cancer | T cells and NK cells | Enhanced apoptosis of CD8+ T cells; suppressed proliferation of CD4+ T cells; decreased NKG2D in NK cells | [46] | |
Melanoma cancer | miRNAs | CD4+ T cells | Enhanced apoptosis of CD4+ T cells | [69] |
Non-small cell lung cancer | mutant KRAS DNA | CD4+ T cells | Conversion of naïve CD4+ T cells into Treg-like cells | [70] |
Breast cancer | lncRNA SNHG16 | T cells | Induction of CD73+γδ1 Tregs | [71] |
Bladdre, colorectal, prostate, breast cancer | CD39, CD73 | T cells | Hydrolysis of ATP and generation of adenosine | [72] |
Hepatocellular carcinoma | HMGB1 | B cells | Expansion of Bregs via TLR2/4-MAPK signaling pathway | [73] |
Pancreatic cancer | TAAs | B cells | Inhibition of complement-dependent and antibody-dependent cell-mediated cytotoxicity | [74] |
Lung cancer | miR-214 | Treg | Suppression of PTEN; Treg expansion | [75] |
Colorectal cancer | miR-208b | Treg | Treg expansion by targeting PDCD4, tumour growth and drug resistance | [76] |
Breast cancer | lncRNA SNHG16 | Vδ1 T cells | Potentiation of the TGF-β1/SMAD5 pathway to upregulate CD73 expression in Vδ1 T cells | [77] |
Ovarian and head and neck squamous cancers | Treg | Increased FasL, IL-10, TGF-β1, CTLA-4, granzyme B and perforin expression and Treg-mediated stronger suppression of T cell proliferation | [78] | |
Nasopharyngeal carcinoma | miR-24-3p; miR-891a; miR-106a-5p; miR-20a-5p; miR-1908 | Treg | Downregulated ERK/STAT1/STAT3 phosphorylation with a shift of T cells towards Treg phenotype | [79] |
Leukemia | 4-1BBL/CD137L | Treg | Elevated expression of effector/tumour Treg markers (CD39, CCR8, CD30, TNFR2, CCR4, TIGIT, IL21R) | [80] |
Pancreatic ductal adenocarcinoma | TGF-β1 | NK cells | Down-regulation of NKG2D, CD107a, TNF-α, INF-γ, CD71, CD98; impaired glucose uptake ability; attenuated NK cell cytotoxic activity | [81] |
Hypoxic lung adenocarcinoma cells | miR-150-5p | NK cells | Down-regulation of CD226 and functional repression of NK cells | [82] |
Pancreatic cancer | miR-212-3p | DCs | Induced immune tolerance via RFXAP | [83] |
Pancreatic cancer | miR-203 | DCs | Inhibition of antigen presentation via TLR4/TNF-α/IL-12 | [84] |
Glioblastoma multiforme | LGALS9 | DCs | Inhibition of antigen recognition, processing and presentation | [85] |
Oral and oropharyngeal squamous cell carcinoma | miR-17-5p, miR-21, miR-16, miR-24, miR-181a, miR-23b | DCs | Impaired differentiation and maturation of mono-DCs | [86] |
Prostate cancer | PGE2 | DCs | Disrupted cytokine production with inhibition of T cell activation, and increased secretion of adenosine with impaired DC functions and direct pro-tumour effects | [87] |
Chronic lymphocytic leukaemia and breast cancer | DCs | Inhibited DC maturation | [88] | |
Melanoma | miR-155, miR-125b, miR-100, miR-146a, miR-146b, let-7e, miR-125a, and miR-99b | MDSCs | Induced immunosuppressive properties | [89] |
Melanoma | HSP86 | MDSCs | TLR4 and NFkB activation on MDSCs, generation of PD-L1+CD11b+Gr1+ MDSCs that suppress T cell functionality | [90] |
Thymoma, mammary carcinoma, and colon carcinoma | Hsp72 | MDSCs | Immunosuppressive signaling via TLR2/STAT3 axis | [76] |
Renal cancer | HSP70 | MDSCs | MDSC proliferation and activation via TLR2 signaling to promote tumour growth and immunosuppression | [77] |
Breast cancer | miR-9, miR-181a | MDSCs | Activated JAK/STAT signaling in eMDSCs through the targeting of SOCS3 and PIAS3 | [78] |
Breast cancer | TGF-β1, PGE2 | MDSCs | MDSC accumulation and accelerated tumour growth | [91] |
Hypoxic glioma cancer cells | miR-10a, miR-21 | MDSCs | Promoted MDSCs expansion and activation through miR-10a/Rora/IκBα/NF-κB and miR-21/Pten/PI3K/AKT pathways | [79] |
Oral squamous cell carcinoma | miR-21 | MDSCs and γδ T cells | Inhibited γδ T cell functions through MDSCs | [92] |
Hypoxic pancreatic cancer cells | miR-301a | Macrophages | M2 polarization via PTEN/PI3Kgamma | [80] |
Lung cancer | miR-103a | Macrophages | M2 polarization | [93] |
Lung cancer | EGFR | Macrophages | Lower host innate antiviral immunity through MEKK2/IRF3 axis | [94] |
Melanoma, lung and squamous skin cancers | Let-7a | Macrophages | Increased OXPHOS activity and TAM via AKT/mTOR | [95] |
p53-mutant cancer cells | miR-1246 | Macrophages | Promoted TAM phenotype | [96] |
Melanoma | miR-125b-5p | Macrophages | Promoted survival via LIPA | [97] |
Hypoxic pancreatic cancer cells | miR-301a-3p | Macrophages | Induced M2 phenotype via PTEN/PI3K signaling | [80] |
Pancreatic cancer | Arachidonic acid | Macrophages | Promoted M2 phenotype | [98] |
Pancreatic cancer cells undergoing ferroptosis | KRASG12D protein | Macrophages | Promoted M2 polarization through STAT3-dependent fatty acid oxidation | [99] |
Pancreatic cancer | miR-155-5p | Macrophages | TAM formation via EHF/Akt/NF-kB axis | [100] |
Metastatic osteosarcoma cells | Macrophages | Induced M2 polarization and impaired phagocytosis, efferocytosis, and macrophage-dependent tumour cell killing | [101] | |
Non-small cell lung cancer | Macrophages | Induced M2 polarization and via PD-L1/HIF1α | [102] | |
Colorectal cancer | miR-25-3p, miR-130b-3p, miR-425-5p | Macrophages | Induced M2 polarization through suppression of PTEN and activation of PI3K/Akt signaling and contributed to the establishment of liver metastasis | [103] |
Colorectal cancer | Macrophages | Mixed M1/M2 secretion pattern | [104] | |
Breast cancer | gp130 | Macrophages | Promoted activation of STAT3 signaling, and enhanced the levels of protumourigenic cytokines and the survival of macrophages | [105] |
Liver cancer cells undergoing ER stress | Macrophages | Promoted secretion of IL-6, MCP-1, IL-10 and TNF-α in macrophages through STAT3 signaling | [106] | |
Breast cancer cells undergoing ER stress | miR-27a-3p | Macrophages | Increase in PD-L1 expression in macrophages | [107] |
Breast cancer | Macrophages | Activation of NF-κB pathway in macrophages, and enhanced levels of IL-6, TNF-α, GCSF, and CCL2 in a TLR2-dependent manner | [108] | |
Gastric cancer | Macrophages | Activation of NF-κB and expression of the proinflammatory factors IL-6, TNF-α, and CCL2 in macrophages to promote tumour progression | [109] | |
Lung cancer | miR-21, miR-29a | Macrophages | Pro-metastatic inflammatory response by serving as ligands of TLR receptors in macrophages; NF-κB activation and increasing the secretion of IL-6 and TNF-α | [110] |
Hypoxic ovarian cancer cells | miR-21-3p, miR-125b-5p, miR-181d-5p | Macrophages | Differentiation into TAM | [111] |
Chronic lymphocytic leukemia (CLL) | Non coding Y RNA hY4 | Monocytes | Increased PD-L1 | [49] |
Pancreatic cancer | Monocytes | Decreased HLA-DR expression, induced arginase and ROS | [112] | |
Snail-expressing head and neck squamous cell carcinoma | miR-21 | Monocytes | M2 polarization | [113] |
Glioblastoma stem cells | Monocytes | M2 polarization and enhanced PD-L1 expression | [114] | |
Gastric cancer | Monocytes | Monocyte differentiation into PD-1+ TAMs, which suppress CD8+ T cell functions | [115] | |
Multiple myeloma | HDGF | Monocytes | MDSCs with suppressive functions | [116] |
Neuroblastoma | miR-21 | Monocytes | Trigger TLR8 with increased miR-155 which transfer to tumour cells leads to drug resistance | [117] |
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Reale, A.; Khong, T.; Spencer, A. Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment. J. Clin. Med. 2022, 11, 6892. https://doi.org/10.3390/jcm11236892
Reale A, Khong T, Spencer A. Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment. Journal of Clinical Medicine. 2022; 11(23):6892. https://doi.org/10.3390/jcm11236892
Chicago/Turabian StyleReale, Antonia, Tiffany Khong, and Andrew Spencer. 2022. "Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment" Journal of Clinical Medicine 11, no. 23: 6892. https://doi.org/10.3390/jcm11236892