MiR-130a and miR-145 reprogram Gr-1⁺CD11b⁺ myeloid cells and inhibit tumor metastasis through improved host immunity.

ABSTRACT: Tumor-derived soluble factors promote the production of Gr-1⁺CD11b⁺ immature myeloid cells, and TGF? signaling is critical in their immune suppressive function. Here, we report that miR-130a and miR-145 directly target TGF? receptor II (T?RII) and are down-regulated in these myeloid cells, leading to increased T?RII. Ectopic expression of miR-130a and miR-145 in the myeloid cells decreased tumor metastasis. This is mediated through a downregulation of type 2 cytokines in myeloid cells and an increase in IFN?-producing cytotoxic CD8 T lymphocytes. miR-130a- and miR-145-targeted molecular networks including TGF? and IGF1R pathways were correlated with higher tumor stages in cancer patients. Lastly, miR-130a and miR-145 mimics, as well as IGF1R inhibitor NT157 improved anti-tumor immunity and inhibited metastasis in preclinical mouse models. These results demonstrated that miR-130a and miR-145 can reprogram tumor-associated myeloid cells by altering the cytokine milieu and metastatic microenvironment, thus enhancing host antitumor immunity.

SUBMITTER: Ishii H 

PROVIDER: S-EPMC6031699 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature