TLR2-Mediated Expansion of MDSCs Is Dependent on the Source of Tumor Exosomes

Abstract

Exosomes released from tumor cells having been shown to induce interleukin-6 release from myeloidderived suppressor cells in a Toll-like receptor 2/Stat3-dependent manner. In this study, we show that exosomes released from tumor cells re-isolated from syngeneic mice are capable of inducing interleukin-6 in a Toll-like receptor 2-independent manner, whereas the data generated from exosomes of tumor cells having undergone numerous in vitro passages induce interleukin-6 in a Toll-like receptor 2-dependent manner. This discrepancy may be due to the source of tumor cells used to generate the exosomes for this study. These results suggest that exosomes released from tumor cells that are not within a tumor microenvironment may not realistically represent the role of tumor exosomes in vivo. This is an important consideration since frequently passing tumor cells in vivo is an accepted practice for studying tumor exosome-mediated inflammatory responses.

Body Fluid Exosomes Promote Secretion of Inflammatory Cytokines in Monocytic Cells via Toll-like Receptor Signaling

“…This is based on the following findings: (i) the stable knockdown of TLR2 or TLR4 led to a partial reduction of cytokine gene induction and release; (ii) antibodies to TLR2 and TLR4 alone could block in part the phosphorylation of STAT3 and subsequent induction of IL-1␤ and IL-6 transcription, but the effect was strongest when both antibodies were used in combination; (iii) human exosomes could trigger secretion of cytokines in mouse DCs and macrophages, but this was abolished in cells deficient for MyD88, an adaptor protein required for TLR signaling. Our results confirm and extend previous work demonstrating a functional role of TLR2 (25,30). For the first time we also show an involvement of TLR4.…”

“…Exosomes Exposure Triggers NFB and STAT3 ActivationPrevious work had shown that ex vitro-derived exosomes from tumor cell lines could trigger NFB signaling (31,36) and activate STAT3 (25,30). In THP-1 cells we investigated the signaling events triggered by exosomes.…”

“…Recent work has shown that the induction of MDSCs from precursors involved TLR signaling and STAT3 activation (25,30). Another study has shown that miRNAs in cancer-released exosomes can reach and bind TLRs and induce prometastatic inflammatory responses (31).…”

The exosomes in tumor immunity

“…These exosomes stimulated TLR2 to activate NF-kB pathway in macrophages, resulting in the secretion of pro-inflammatory cytokines such as IL-6, TNF-a, and CCL2. 35 Additionally, exosomes contain large amounts of small non-coding RNAs, especially miRNAs, which can function as agonists of RNA-binding TLRs. TLR7 and TLR8 were found to recognize exosome-derived miRNAs and stimulate downstream NF-kB pathway and inflammatory cytokine secretion in macrophage.…”

Tumor Exosome-Mediated MDSC Activation

“…In a recent issue of The American Journal of Pathology, Xiang et al 1 published their results concerning the effects of tumor-derived exosomes on myeloid-derived suppressor cell (MDSC) biology. They compared the biological effects of exosomes derived from in vitro cultured B16 tumor cells (termed C-exo for culture exosome) and exosomes derived from in vivo grown B16 tumor (termed P-exo for primary exosomes).…”