The role of tumor-derived exosomes in the differentiation, maturation and functional changes of dendritic cells

Recently, researchers at Isfahan Medical University in Iran published an article titled "The roles of tumor-derived exosomes in altered differentiation, maturation and function of dendritic cells" in Molecular Cancer
.
Tumor-derived exosomes (TDEs) have been shown to block the anti-tumor immune response through their immunosuppressive cargo
.
Because dendritic cells (DC) are the key mediators that initiate and maintain T cell-mediated responses, it is logical that exosomes released by tumor cells play a leading role in DC biology
.
This paper aims to provide a mechanical insight into TDES-mediated dendritic cell abnormalities in the context of tumors
.
More importantly, the author extensively discussed how tumor exosomes induce DC differentiation, maturation and functional subversion on different sections
.
The author also briefly described the importance of TDEs at the therapeutic level to help guide future treatment options, especially DC-based vaccination strategies, and reviewed the progress in the design and discovery of exosome inhibitors
.
Understanding the content of extracellular bodies and the ways in which TDEs lead to immune evasion may help to revise treatment principles and design new treatment methods to overcome obstacles in cancer treatment
.

Image source: https://doi.
org/10.
1186/s12943-021-01376-w

Extracellular bodies are nanometer- sized (30-150 nm) extracellular vesicles, released by almost all types of cells, and their content strongly reflects the content of the parent cell
.
In particular, tumor cells have been shown to actively secrete large amounts of exosomes to provide intercellular communication with surrounding and distant cells
.
These extracellular vesicles contain several types of mRNA, microrna, functional surface proteins, enzymes and lipids, which enable them to interact directly with cell surface receptors or through plasma membrane fusion, endocytosis, phagocytosis, microphagocytosis And lipid raft-mediated internalization transfers its content to recipient cells to exert local or systemic effects
.
Convincing evidence shows that tumor-derived exosomes (TDEs) contribute to tumor progression and play a vital role in almost all aspects of tumor development, such as angiogenesis, proliferation, and metastasis
.

In addition, TDES also promotes tumor growth by negatively regulating the anti-cancer immune response
.
Some studies have shown that TDEs can inhibit anti-tumor immunity through internalization of target cells or through receptor-ligand interactions
.
In this regard, it has been recognized that TDEs containing too many membrane-bound proteins (Fas-L, PD-L1, etc.
) can directly inhibit the anti-tumor activity of effector CD8+ T cells and NK cells
.
On the other hand, more importantly, the exosomes released by tumor cells can also be absorbed or interacted with by antigen presenting cells (APCs), thereby indirectly inducing antigen-specific tolerance
.
It is particularly noteworthy that TDEs specifically target dendritic cells (DC), which are the most important and effective APCs, and coordinate the immune response by activating initial T cells and providing follow-up signals required for effector T cell activity
.
In this regard, studies have shown that TDEs largely inhibit the differentiation of DCs into bone marrow progenitor cells and monocytes, and strongly promote the development of tumor supporting cells, such as myeloid-derived suppressor cells (Mdscs)
.
Tumor-derived exosomes also carry several biologically active molecules that can interfere with the maturation of dendritic cells, thereby destroying their ability to induce effective anti-tumor responses
.
In addition, studies have also shown that TDEs can change the function of well-differentiated mature DCs
.
According to published data, the interaction/uptake of mature DCs and TDEs makes them exhibit an immunosuppressive phenotype, which can improve the immune escape of tumors
.

On the contrary, because TDEs contain a variety of tumor-associated antigens, it is generally believed that exosomes released by cancer cells can stimulate DC to support the development of powerful anti-tumor immunity
.
However, more and more evidence shows that the main effect of TDEs is immunosuppression, not immune stimulation
.
In summary, TDES seems to have a negative impact on DC, which is a key mediator of the immune response, thereby preventing the formation of effective anti-tumor immunity
.
However, the literature review on the molecular mechanism of tumor- derived exosomes interfering with dendritic cell biology is still lacking
.
Therefore, in this study, the authors provide public evidence of how TDEs impair the differentiation, maturation and function of DCs
.
Then, the author briefly discussed the lessons learned from TDEs-mediated DC aberrations to translate research into practice, and reviewed the progress in the design and development of exosome inhibitors as potential cancer adjuvant treatments
.

Tumor- derived exosomes inhibit the differentiation of dendritic cells

Image source: https://doi.
org/10.
1186/s12943-021-01376-w

The literature reviewed in this article shows that TDEs impair the differentiation, maturation and function of DCs, and are beneficial to immune escape and tumor growth
.
Although this article discusses several clear and proven mechanisms of tumor exosomes on the biological inhibition of DCs, TDES may also change the behavior of DCs through some speculative mechanisms
.
For example, blocking the differentiation of dendritic cells is mainly due to the presence of tumor-derived vascular endothelial growth factor (VEGF), and its level is negatively correlated with the number of dendritic cells in human cancer circulation and TME
.
Tumor-derived exosomes have also been shown to induce the release of VEGF by transferring miRNA 21 to recipient cells, leading to an increase in the level of VEGF in tumors
.
Recent research results also show that TDES contains an active VEGF subtype, which is related to tumor growth and resistance to common monoclonal antibody (MAb) therapy
.
In addition, tumor cells also secrete excessive gangliosides GD2 and GM3, which inhibit the differentiation of DCs into CD34+ and monocyte precursors, and induce apoptosis of monocyte-derived DCs
.
These sialic acid-containing glycosphingolipids have also been shown to be shed from tumors through exosomes and can actively suppress immune cells
.
Therefore, it can be speculated that several other extracellular biomolecules, including but not limited to VEGF, miRNA-21 and gangliosides, may play a role in DC differentiation disorders in the context of tumors; however, their role remains to be studied
.
In addition, it is reported that tumor exosomes also contain significant amounts of IL-10
.
High levels of IL-10 block the initiation of T cell responses by down-regulating the expression of MHC-I and costimulatory molecules, thereby inhibiting the maturation of DCs
.
However, so far, there is no evidence that IL-10 plays a role in TDES-mediated DC defects
.
Future research can clarify the connection between the above-mentioned exosomal markers and DC abnormalities in cancer
.
In addition, because different DC subgroups show different phenotypic characteristics and functional potential, it will be very important to pay more attention to the influence of TDES on DC subgroups in future research
.
In addition, as discussed later in this review, great efforts have been made so far to target exosomes or exosomal markers to inhibit tumor progression and improve anti-tumor immunity
.
However, despite the significant progress made in the discovery of exosome inhibitors in recent years, it is still in its infancy, and the therapeutic value of these inhibitors as adjuvant cancer treatments has not yet been fully verified
.
Most of the compounds tested to inhibit exosomes are highly cytotoxic and have not shown selective inhibition of tumor exosomes, so they may interfere with cell-to-cell communication by inhibiting the secretion of exosomes from non-tumor cells , Resulting in unwanted side effects
.
Therefore, there are still major challenges in finding new compounds and viable targets that selectively inhibit or remove tumor exosomes
.
In short, more and more evidence supports the view that tumor- derived exosomes are potential inhibitors of immune cells, including DC, and targeting these extracellular vesicles may provide a new way to better treat cancer.
Way
.
( Bioon.
com)

Reference

Reza Hosseini et al.
The roles of tumor-derived exosomes in altered differentiation, maturation and function of dendritic cells.
Mol Cancer.
2021 Jun 2; 20(1): 83.
doi: 10.
1186/s12943-021-01376-w.