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

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Abstract

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.

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Acknowledgments

The work was supported by the National Natural Science Foundation of P. R. China (Grant No. 81272572). The authors thank Prof Chun-Li Luo, Xue Yang and Xue-Dong Song for the skillful technical help (College of Laboratory Medicine, Chongqing Medical University, Chongqing, China).

Conflict of interest

The authors declare that there is no conflict of interests.

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Authors and Affiliations

  1. Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, People’s Republic of China

    Jianjun Diao, Shiyou Chen, Yunfeng He, Qingsong Wang, Gang Chen, Xiaohou Wu & Yao Zhang

  2. The Key Laboratory of Diagnostics Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, People’s Republic of China

    Xue Yang, Xuedong Song & Chunli Luo

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  1. Jianjun Diao
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  2. Xue Yang
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  4. Shiyou Chen
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  7. Gang Chen
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  9. Xiaohou Wu
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Correspondence to Xiaohou Wu or Yao Zhang.

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Diao, J., Yang, X., Song, X. et al. Exosomal Hsp70 mediates immunosuppressive activity of the myeloid-derived suppressor cells via phosphorylation of Stat3. Med Oncol 32, 35 (2015). https://doi.org/10.1007/s12032-014-0453-2

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