Emerging Role of Extracellular Vesicles in Immune Regulation and Cancer Progression
Abstract
:Simple Summary
Abstract
1. Introduction
2. Impact of Extracellular Vesicles on Different Immune Cells
3. Functional Regulation of Immune Cells by Tumor-Derived Extracellular Vesicles
3.1. Tumor-Derived Extracellular Vesicles and Suppression of the Antitumor Immune Response
- (a)
- Impaired antigen presentation: Tumor cells express antigens called tumor-associated antigen (TAA), which could be either mutated or abnormal proteins with distinct post-translational modifications. TAA and their peptides are presented to the cell surface by MHC I complex are recognized and destroyed by cytotoxic T lymphocytes (CTLs), resulting in cancer cell killing [32]. However, cancer cells can escape from this destruction. This is achieved by downregulating MHC I expression, which may affect the antigen processing machinery and leads to defective antigen presentation. Thus, the cancer cell lacking target antigen/MHC I expression is no longer recognized by CTLs but eventually recognized and destroyed by NK cells according to the missing-self hypothesis [33]. To escape from NK cell-mediated killing, cancer cells may release EVs that affect the NK cell-mediated cytotoxicity by regulating the expression of NK cell-activating NKG2D receptor [34]. NKG2D receptor interacts with its ligands MIC-A and MIC-B (MHC class I chain-related proteins A and B) and UL-16 binding proteins (ULBPs). EVs carrying NKG2D ligands (MIC-A/B and ULBPs) decrease the NKG2D expressions on NK cells and impair NKG2D-mediated NK cell cytotoxicity in acute myeloid leukemia, mesothelioma, prostate, and breast cancer cells [34,35,36].
- (b)
- Inhibition of antigen-presenting cells and cytotoxic T cell- EVs derived from sera of melanoma and head and neck cancer patients inhibited the proliferation of CD8+ CTLs. The importance of FasL-, TNF-related apoptosis-inducing ligand(TRAIL-), and PD-L1-containing vesicles in inducing T cell apoptosis has been demonstrated by various scientific groups, including annexin V binding, cytochrome c release from mitochondria, loss of the mitochondrial membrane potential, caspase 3-cleavage, and DNA fragmentation [37,38,39]. TD-EVs also targets the PI3k/AKT pathway in activated CD8+ T cells by Akt dephosphorylation, which leads to the activation of pro-apoptotic protein Bax and downregulates anti-apoptotic Bcl-2 family members [40]. Moreover, EVs can modulate gene expression profile and function of recipient cells by transferring nucleic acids, especially mRNA and miRNAs. In a study by Muller et al., the EVs from cancer cells induced changes in mRNA expression levels of immune function-related genes in activated T cells. The incubation of TD-EVs with human CD4+ CD39+ Treg cells, a subset of CD4+T cells; conventional CD4+ T cells, or CD8+ T lymphocytes increased the expression of immunosuppressive molecules, such as TGF-β, IL-10, COX-2, CD39, and CD73 [41]. The role of TD-EVs carrying miRNA in immunosuppression has been described in a few studies. For instance, overexpression of five miRNAs was reported in EVs derived from nasopharyngeal carcinoma cells. These overexpressed miRNAs reduced the MAPK signaling in T cells, leading to impaired T cell proliferation and differentiation [42]. Moreover, miRNA from TD-EVs also regulates the activity of other immune cells, such as NK cells, B cell monocytes, and DCs ( reviewed by Michael W Graner) [43]. TD-EVs also regulate the function of mesenchymal stem cells (MSCs), which support cancer progression by creating an immunosuppressive microenvironment. For instance, heat shock protein (Hsp)70 on the surface of EVs from lung tumor cells activated NF-κB signaling and elevated the secretion of proinflammatory cytokines by MSCs, thus promoting tumor growth [44]. Furthermore, TD-EVs carrying enzymatically active ectonucleotidases CD39 and CD73 suppress the activation of T cells and B cells. CD39 and CD73 secrete an immunosuppressive factor, adenosine, and negatively regulate the immune response [41,45].
- (c)
- Effects on differentiation of immune cells: EVs derived from breast cancer cells increased the TGFβ-mediated phosphorylation of Smad2/3 and STAT3 in T cells, thereby changing the phenotype to Treg cells [46]. TGFβ is one of the major immunosuppressive cytokines present on the surface of EVs. TD-EVs-associated TGFβ1 suppressed the activity of NK cells by lowering the NKG2D expression in AML patients and suppressed T cell proliferation in breast cancer [46,47,48]. EVs derived from human multiple myeloma cells, renal cells, and murine breast carcinomas triggered the differentiation and proliferation pathways in MDSCs, which depends on the activation of STAT3 signaling and also the presence of prostaglandin E2 PGE2, Hsp72, and TGF-β in the TD-EVs cargo [7,49,50]. Furthermore, EVs derived from ovarian, pancreatic, and colon cancers shift cancer-suppressive M1 macrophage to a tumor-supportive M2 phenotype [51,52]. Overall, these findings support the immunosuppressive ability of TD-EVs that negatively regulate the function of immune cells by transferring bioactive molecules, such as nucleic acids and/or proteins.
3.2. Tumor-Derived Extracellular Vesicles Stimulate the Immune Response
4. Immune Cells Derived Extracellular Vesicles
4.1. B Cell-Derived Extracellular Vesicles
4.2. DC-Derived Extracellular Vesicles
4.3. T Cell-Derived Extracellular Vesicles
4.4. NK Cell-Derived Extracellular Vesicles
5. Extracellular Vesicles in Tumor Microenvironment Remodeling
6. Extracellular Vesicles in Transcriptional Regulation
7. Tumor-Derived Extracellular Vesicles Mediate Resistance to Immunotherapy
8. Extracellular Vesicles as a Carrier of Cancer Therapy
9. Extracellular Vesicles as a Biomarker in Cancer
10. Conclusions and Future Perspectives
Funding
Conflicts of Interest
Abbreviations
TD-EVs | Tumor-derived extracellular vesicles |
TAA | Tumor-associated antigens |
DC | Dendritic cell |
CTL | Cytotoxic T lymphocytes |
APC | Antigen-presenting cell |
EVs | Extracellular vesicles |
SPHK1 | Sphingosine kinase 1 |
FasL | Fas ligand |
DC-EVs | DC-derived extracellular vesicles |
MSC | Mesenchymal stem cells |
MHC | Major histocompatibility complex |
MDSC | Myeloid-derived suppression cell |
NK | Natural killer cells |
TNF-α | Tumor necrosis factor alpha |
TRAIL | TNF-related apoptosis-inducing ligand |
TGF-β | Tumor growth factor beta |
VEGF | Vascular endothelial growth factor |
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Mittal, S.; Gupta, P.; Chaluvally-Raghavan, P.; Pradeep, S. Emerging Role of Extracellular Vesicles in Immune Regulation and Cancer Progression. Cancers 2020, 12, 3563. https://doi.org/10.3390/cancers12123563
Mittal S, Gupta P, Chaluvally-Raghavan P, Pradeep S. Emerging Role of Extracellular Vesicles in Immune Regulation and Cancer Progression. Cancers. 2020; 12(12):3563. https://doi.org/10.3390/cancers12123563
Chicago/Turabian StyleMittal, Sonam, Prachi Gupta, Pradeep Chaluvally-Raghavan, and Sunila Pradeep. 2020. "Emerging Role of Extracellular Vesicles in Immune Regulation and Cancer Progression" Cancers 12, no. 12: 3563. https://doi.org/10.3390/cancers12123563