Exosomal Hsp70 mediates immunosuppressive activity of the myeloid-derived suppressor cells via phosphorylation of Stat3.

Myeloid-derived suppressor cells (MDSCs), one of the main cell populations, are responsible for regulating the immune response, which accumulates in tumor-bearing mice and humans contributing to cancer development. Exosomes produced by tumor cells have been involved in tumor-associated immune suppression. However, the role of exosomes is unclear in the activation of MDSCs. Here, we have purified tumor-derived exosomes from the supernatants of Renca cell cultures. Transmission electron microscopy was used to confirm their morphology, and Western blot analysis showed that Hsp70 was rich in these isolated exosomes compared with the whole-cell lysates of Renca cells. Then, we demonstrated that there was a more powerful activity of exosomal Hsp70-mediated induction of proinflammation cytokines, tumor growth factors of MDSCs and tumor progression than exosomes pre-incubated with anti-Hsp70 antibody. Furthermore, we show that an interactive exosomal HSP70 and MDSCs determine the suppressive activity of the MDSCs via phosphorylation of Stat3 (p-Stat3). Finally, we show that exosomal Hsp70 triggers p-Stat3 in MDSCs in a TLR2-MyD88-dependent manner. Meanwhile, we also find that there is a more significant increase in the percentage of CD11b+Gr-1+ cells in the mice, which are treated with exosomal Hsp70 than that exosomes pre-incubated with anti-Hsp70 antibody. Hence, we believe that the signaling pathway activation by exosomal Hsp70 within MDSCs may be a significant target in future treatment of renal cell carcinoma.