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

  • Nat Commun. 2018 Jul 4;9(1):2611. doi: 10.1038/s41467-018-05023-9.
Hiroki Ishii  1 ,  Suman K Vodnala  1 ,  Bhagelu R Achyut  1  2 ,  Jae Young So  1 ,  M Christine Hollander  1 ,  Tim F Greten  3 ,  Ashish Lal  4 ,  Li Yang  5
Affiliations
  • 1. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
  • 2. Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, 30912, USA.
  • 3. Gastrointestinal Malignancy Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
  • 4. Genetic Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
  • 5. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA. [email protected].
PMID: 29973593 DOI: 10.1038/s41467-018-05023-9
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.

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