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.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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CD11b Antigen / genetics
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CD11b Antigen / immunology
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / pathology
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Cell Line, Tumor
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Drug Evaluation, Preclinical
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Immunity, Innate / drug effects*
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Injections, Intravenous
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Lung Neoplasms / genetics*
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Lung Neoplasms / immunology
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Lung Neoplasms / secondary
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Lung Neoplasms / therapy
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Mammary Neoplasms, Experimental / genetics*
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Mammary Neoplasms, Experimental / immunology
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Mammary Neoplasms, Experimental / pathology
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Mammary Neoplasms, Experimental / therapy
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Mice
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Mice, Transgenic
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MicroRNAs / genetics*
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MicroRNAs / immunology
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Myeloid Cells / drug effects
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Myeloid Cells / immunology
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Myeloid Cells / pathology
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Oligoribonucleotides / administration & dosage
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Oligoribonucleotides / genetics
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Oligoribonucleotides / metabolism
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Pyrogallol / analogs & derivatives
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Pyrogallol / pharmacology
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / immunology
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Receptor, Transforming Growth Factor-beta Type II / genetics*
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Receptor, Transforming Growth Factor-beta Type II / immunology
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Receptors, Chemokine / genetics
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Receptors, Chemokine / immunology
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Signal Transduction
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Sulfonamides / pharmacology
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / immunology
Substances
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Antineoplastic Agents
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CD11b Antigen
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Gr-1 protein, mouse
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MIRN130 microRNA, mouse
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MIRN145a microRNA, mouse
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MicroRNAs
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NT157 compound
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Oligoribonucleotides
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Receptors, Chemokine
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Sulfonamides
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Transforming Growth Factor beta
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Pyrogallol
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Interferon-gamma
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Receptor, IGF Type 1
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Receptor, Transforming Growth Factor-beta Type II