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

Hiroki Ishii, Suman K. Vodnala, Bhagelu R. Achyut, Jae Young So, M. Christine Hollander, Tim F. Greten, Ashish Lal and Li Yang ()
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Hiroki Ishii: National Cancer Institute, NIH
Suman K. Vodnala: National Cancer Institute, NIH
Bhagelu R. Achyut: National Cancer Institute, NIH
Jae Young So: National Cancer Institute, NIH
M. Christine Hollander: National Cancer Institute, NIH
Tim F. Greten: National Cancer Institute, NIH
Ashish Lal: National Cancer Institute, NIH
Li Yang: National Cancer Institute, NIH

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Tumor-derived soluble factors promote the production of Gr-1+CD11b+ immature myeloid cells, and TGFβ signaling is critical in their immune suppressive function. Here, we report that miR-130a and miR-145 directly target TGFβ receptor II (TβRII) and are down-regulated in these myeloid cells, leading to increased TβRII. 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 IFNγ-producing cytotoxic CD8 T lymphocytes. miR-130a- and miR-145-targeted molecular networks including TGFβ 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.

Date: 2018
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DOI: 10.1038/s41467-018-05023-9

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