Contribution of MyD88 to the Tumor Exosome-Mediated Induction of Myeloid Derived Suppressor Cells

Abstract

In this study we observed that mice pretreated with tumor exosomes had a significant acceleration of tumor metastasis in the lung. Tumor metastasis correlated significantly with an increase in recruitment of more Myeloid-derived suppressor cells (MDSCs) in the lung of C57BL/6j (B6) mice pretreated with tumor exosomes. These effects were blunted when MyD88 knockout (KO) mice were pretreated with tumor exosomes. MDSCs induced by tumor exosomes and isolated from wild-type B6 mice also more potently inhibited T cell activation and induction of interleukin-6 and tumor necrosis factor-alpha than MDSCs isolated from the lung of MyD88 KO mice. In vitro, addition of tumor exosomes to bone marrow-derived CD11b(+)Gr-1(+) cells isolated from wild-type B6 mice resulted in more cytokine production, including tumor necrosis factor-alpha, interleukin-6, and the chemokine CCL2, than CD11b(+)Gr-1(+) cells isolated from MyD88 KO mice. Moreover, lower levels of CCL2 were observed in the lungs in MyD88 KO mice pretreated with tumor exosomes than that in wild-type mice. Together these data demonstrate a pivotal role for MyD88 in tumor exosome-mediated expansion of MDSCs and tumor metastasis.

Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid‐derived suppressor cells

“…39 Data obtained in mouse studies suggest that specific cytokines, including GM-CSF and IL-6, are responsible for the in vitro generation of MDSCs from human PBMC. 21 Interestingly, although Myd88, a cytoplasmic adaptor molecule essential for TLR-mediated signaling, was reported to be involved for tumor exosome-mediated generation of MDSCs, anti-CD3 Ab-mediated proliferation of CD8 þ T cells was not significantly reduced by CD11b þ Gr-1 þ cells obtained from exosome-treated Myd88 À/À mice, 40 suggesting MDSC could acquire an immunostimulatory phenotype in the absence of MyD88 signaling similar to our current results.…”

The Multiple Roles of Exosomes in Metastasis

“…However, most investigations on immune-mechanisms based promotion of metastasis were performed with TC-derived exosomes. Melanoma cell line B16-derived exosomes induced a switch in differentiation to COX2, IL6, VEGF and arginase expressing MDSCs, in a manner that was dependent on MyD-88, an adaptor molecule that is involved in the Toll-like receptor family signaling (125,126). Inhibition of T-cell activation and acceleration of metastasis to the lung was noted in mice treated with TC-derived exosomes and the effects were blunted in MyD88 knock-out mice.…”

“…However, a serious limitation for translational research is the complexicity of pre-metastatic and metastatic niches with respect to its architecture and the interplay between secreted factors and cellular components, resulting in difficulties in setting up in vitro systems for its recapitulation for discovery of inhibitory molecules. Demonstration of existence of pre-metastatic niche (52) Exosomes as instigators of metastatic niche formation (86,98) Bone marrow education by exosomes increases metastatic burden (86) Horizontal transfer of exosomal MET to bone marrow progenitors (86) Interplay between tumor cells and astrocytes (113), endothelial cells (106,107,109,110,111) and fibroblasts (106,107,109,110,111) induces metastasis Exosomes enhance metastasis by immuno-suppression (125,126) Exosomes mediate organ tropism of metastasis (134) …”

The exosomes in tumor immunity

“…26 Detailed mechanisms of the inhibition have focused on protein contents in exosomes, such as TGF-b, IL-6, PGE2 and so on. [25][26][27] Moreover, mice pretreated with TEXs also showed an accumulation of MDSCs in spleen, peripheral blood and lung. 28 Interestingly, heat shock protein 72 (HSP72) expressed at the surface of TEXs could induce activation of Stat3 and production of IL-6 in a TLR2/MyD88-dependent manner, thus promoting suppressive functions of MDSCs.…”

“…24 When added to the classical in vitro culture system of mouse DCs, TEXs inhibited the differentiation of BM myeloid precursors into DCs via induction of IL-6. 25 In addition, exosomes from human cancers also induced CD14 C monocytes to differentiate into CD14 C HLA-DR ¡/low cells, which suppressed T cell proliferation and cytolytic functions. 26 Detailed mechanisms of the inhibition have focused on protein contents in exosomes, such as TGF-b, IL-6, PGE2 and so on.…”