Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis

Acquired resistance to chemotherapy remains a major stumbling block in cancer treatment. Chronic inflammation plays a crucial role in induction of chemo resistance, and results in part from the induction and expansion of inflammatory cells that include myeloid derived suppressor cells (MDSC) and IL-13(+)Th2 cells. The mechanisms that lead to induction of activated MDSCs and IL-13(+)Th2 cells have not yet been identified. Here we demonstrated that doxorubicin treatment of 4T1 breast tumor bearing mice led to the induction of IL-13R(+)miR-126a(+)MDSC (DOX-MDSC). DOX-MDSC promote breast tumor lung metastasis through MDSC miR-126a(+)exosomal mediated induction of IL-13(+)Th2 cells and tumor angiogenesis. The induction of DOX-MDSC is regulated in a paracrine manner. DOX treatment not only increases IL-33 released from breast tumor cells, which is crucial for the induction of IL-13(+)Th2 cells, but it also participates in the induction of IL-13 receptors and miR-126a expressed on/in the MDSCs. IL-13 released from IL-13(+)Th2 cells then promotes the production of DOX-MDSC and MDSC miR-126a(+)exosomes via MDSC IL-13R. MDSC miR-126a(+)exosomes further induce IL13(+)Th2 cells in a positive feed-back loop manner. We also showed that MDSC miR-126a rescues doxorubicin induced MDSC death in a S100A8/A9 dependent manner and promotes tumor angiogenesis. Our findings provide insight into the MDSC exosomal mediated chemo resistance mechanism, which will be useful for the design of inhibitors targeting the blocking of induction of miR-126a(+)MDSC.