Abstract
The biology of tumor-derived exosomes (TEX) is only partially understood and much remains to be studied in order to define the effect that the tumor microenvironment or the activation of tumor cells exerts on their composition and functions. Increased expression and activity of toll-like receptor 4 (TLR4) in chronic infectious and inflammatory conditions is related with cancer progression: its activation induces an inflammatory signaling that increases the tumorigenic potential of cancer cells promoting their immune evasion. We investigated the immune modulatory properties of TEX released upon cell TLR4 activation, and we found that, although differences were observed depending on the type of the tumor, the treatment influences TEX composition and boosts their immunosuppressive ability. Our results suggest that the activation of TLR4 supports tumor progression by stimulating the release of more effective immunosuppressive exosomes, which allow tumor cells to escape immune surveillance and probably even play a role in the metastatic process.
Highlights
The immunological activities of tumor-derived exosomes (TEX) influences immune regulation mechanisms, including modulating antigen presentation, immune activation, immune suppression, immune surveillance, and intercellular communication[5,6]
Our results show that the activation of toll-like receptor 4 (TLR4) supports tumor progression by promoting the release of more effective immunosuppressive exosomes, differences were observed depending on the origin of the tumor
To investigate the molecular mechanisms underlying the inhibitory effects of exosomes released by tumor cells upon TLR4 activation by LPS, we examined whether TGFβ was present on exosome surface, as this cytokine is strongly implicated in mechanisms of immune evasion and may be responsible for the antiproliferative effect www.nature.com/scientificreports observed in our study
Summary
The immunological activities of TEX influences immune regulation mechanisms, including modulating antigen presentation, immune activation, immune suppression, immune surveillance, and intercellular communication[5,6] Their molecular cargo partially derived from the surface of parent tumor cells and is enriched in immunosuppressive proteins (i.e. FasL, PD-L1, inhibitory cytokines, PGE2) as well as tumor-associated-antigens and co-stimulatory molecules[7]. The molecular profile endows TEX with a dual ability of mediating either immune suppression or immune stimulation, presumably depending on the microenvironment influences on their parental cells[3]. Www.nature.com/scientificreports origin that have lately arisen as potential endogenous ligands of TLR4 These proposed endogenous molecules include different components of the extracellular matrix, intracellular proteins, or modified lipids or lipoproteins[15]. Our results show that the activation of TLR4 supports tumor progression by promoting the release of more effective immunosuppressive exosomes, differences were observed depending on the origin of the tumor
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