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Review
. 2021 Jun 2;20(1):83.
doi: 10.1186/s12943-021-01376-w.

The roles of tumor-derived exosomes in altered differentiation, maturation and function of dendritic cells

Reza Hosseini  1 , Leila Asef-Kabiri #  2 , Hassan Yousefi #  3 , Hamzeh Sarvnaz  4 , Majid Salehi  5 , Mohammad Esmaeil Akbari  6 , Nahid Eskandari  7
Affiliations
Review

The roles of tumor-derived exosomes in altered differentiation, maturation and function of dendritic cells

Reza Hosseini et al. Mol Cancer. .

Abstract

Tumor-derived exosomes (TDEs) have been shown to impede anti-tumor immune responses via their immunosuppressive cargo. Since dendritic cells (DCs) are the key mediators of priming and maintenance of T cell-mediated responses; thus it is logical that the exosomes released by tumor cells can exert a dominant influence on DCs biology. This paper intends to provide a mechanistic insight into the TDEs-mediated DCs abnormalities in the tumor context. More importantly, we discuss extensively how tumor exosomes induce subversion of DCs differentiation, maturation and function in separate sections. We also briefly describe the importance of TDEs at therapeutic level to help guide future treatment options, in particular DC-based vaccination strategy, and review advances in the design and discovery of exosome inhibitors. Understanding the exosomal content and the pathways by which TDEs are responsible for immune evasion may help to revise treatment rationales and devise novel therapeutic approaches to overcome the hurdles in cancer treatment.

Keywords: Dendritic cell; Exosome; Immunity; Tumor.

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Conflict of interest statement

The authors declare that they have no competing of interests.

Figures

Fig. 1
Fig. 1
Tumor-derived exosomes inhibit differentiation of dendritic cells. Tumor-derived exosomes contain several biomolecules including COX-2 (cyclooxygenase-2), PGE2 (prostaglandin E2), TGF-β (transforming growth factor- β), IL-6, HSP70, HSP72, HLA-G and glycolytic enzymes, thereby could affect bone marrow progenitors and inhibit differentiation of DCs and monocytes, while promoting the polarization of myeloid-derived suppressor cells (MDSCs). Exosomes derived from tumors can also impede monocytes differentiation toward DCs. Mo-DCs: monocyte-derived dendritic cells
Fig. 2
Fig. 2
Tumor-derived exosomes inhibit maturation of dendritic cells. Exosomal galectin-9 can interact with its cognate TIM-3 receptors on DCs and inhibit antigen-sensing by them. The expression of CD47 on TDEs inhibits their phagocytosis by immune cells and improves their retention in the circulation. Exosomal S100A9 downmodulates the maturation of DCs and decrease the expression of co-stimulatory CD83, CD86, IL-12 and IL-15 by DCs. Tumor exosomes induce DCs to express TGF-β, which further increases TGF-β expression in an autocrine loop, and robustly inhibits anti-tumor immunity. Higher levels of glycolytic enzymes detected on TDEs can impair DCs maturation by increasing ATP and lactate levels In TME
Fig. 3
Fig. 3
Tumor-derived exosomes inhibit normal function of dendritic cells. A plethora of inhibitory molecules including PD-L1, CD73, IDO (Indoleamine 2, 3-dioxygenase), L-arginase, PGE2, TGF-β, Lipids, and components of the STAT3 activators is presented in TDEs can reprogram DCs into immunosuppressive players and subvert their function either in priming or sustaining of anti-tumor immune responses. Exosomal PD-L1 interacts with PD-1 expressed on immune cells, including DCs and inhibits their function. IDO and L- arginase degrades tryptophan and arginine, respectively and thereby impedes effective priming of T cells. PGE2 and TGF- β are two inhibitory molecules enriched in TDEs which can impair antigen-presentation activity of DCs. Lipids and the STAT3 activating components can also be transported by TDEs, inducing dysfunctional DCs
Fig. 4
Fig. 4
Combining targeted tumor exosome inhibition or removal with exiting chemo- and immunotherapies. Tumor exosomes induce resistance to chemotherapies and counteract beneficial effects of immunotherapies including monoclonal antibodies (mAbs), adoptive transfer of NK-92 cells and possibly TDE-loaded DCs. Adjunctive inhibition or removal of TDEs may add to the therapeutic benefits of currently available chemo- and immunotherapies and could improve tumor regression
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