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Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer.

ABSTRACT: Modulating the activity of miRNAs provides opportunities for novel cancer interventions. However, low bioavailability and poor cellular uptake are major challenges for delivering miRNA mimetics specifically to tumor cells. Here, we took advantage of the spontaneous enhanced endocytic activity of ovarian cancer-associated dendritic cells (DC) to selectively supplement the immunostimulatory miRNA miR-155. In vivo processing of nanoparticles carrying oligonucleotide duplexes mimicking the bulged structure of endogenous pre-miRNA (but not siRNA-like oligonucleotides) dramatically augmented miR-155 activity without saturating the RNA-induced silencing complex. Endogenous processing of synthetic miR-155 favored Ago2 and, to a lesser extent, Ago4 loading, resulting in genome-wide transcriptional changes that included silencing of multiple immunosuppressive mediators. Correspondingly, tumor-infiltrating DCs were transformed from immunosuppressive to highly immunostimulatory cells capable of triggering potent antitumor responses that abrogated the progression of established ovarian cancers. Our results show both the feasibility and therapeutic potential of supplementing/replenishing miRNAs in vivo using nonviral approaches to boost protective immunity against lethal tumors. Thus, we provide a platform, an optimized design, and a mechanistic rationale for the clinical testing of nonviral miRNA mimetics.

SUBMITTER: Cubillos-Ruiz JR

PROVIDER: S-EPMC3319850 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer.

Cubillos-Ruiz Juan R JR Baird Jason R JR Tesone Amelia J AJ Rutkowski Melanie R MR Scarlett Uciane K UK Camposeco-Jacobs Ana L AL Anadon-Arnillas Jorge J Harwood Noah M NM Korc Murray M Fiering Steven N SN Sempere Lorenzo F LF Conejo-Garcia Jose R JR

Cancer research 20120203 7

Modulating the activity of miRNAs provides opportunities for novel cancer interventions. However, low bioavailability and poor cellular uptake are major challenges for delivering miRNA mimetics specifically to tumor cells. Here, we took advantage of the spontaneous enhanced endocytic activity of ovarian cancer-associated dendritic cells (DC) to selectively supplement the immunostimulatory miRNA miR-155. In vivo processing of nanoparticles carrying oligonucleotide duplexes mimicking the bulged st ...[more]

PMID: 22307839

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Project description:Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infections in infants. Macroautophagy/autophagy is a catalytic metabolic process required for cellular homeostasis. Although intracellular metabolism is important for immune responses in dendritic cells, the link between autophagy and immunometabolism remains unknown. Here, we show that the autophagy-related protein ATG5 regulates immunometabolism. Atg5-deficient mouse dendritic cells showed increased CD8A+ T-cell response and increased secretion of proinflammatory cytokines upon RSV infection. Transcriptome analysis showed that Atg5 deficiency alters the expression of metabolism-related genes. Atg5-deficient dendritic cells also showed increased activation of glycolysis and the AKT-MTOR-RPS6KB1 pathway and decreased mitochondrial activity, all of which are cellular signatures for metabolic activation. These cells also showed elevated CD8A+ T-cell priming and surface major histocompatibility complex (MHC) class I expression. Our results suggested that ATG5 regulated host immune responses by modulating dendritic cell metabolism. These findings may help develop potential antiviral therapies that alter host immunity by regulating autophagy and immunometabolism.Abbreviations : 2-DG: 2-deoxyglucose; AAK1: AP2 associated kinase 1; AKT: AKT serine/threonine kinase; AM: alveolar macrophage; ATG: autophagy; ATP: adenosine triphosphate; BAL: bronchoalveolar lavage; BMDC: bone marrow dendritic cell; CSF2/GM-CSF: colony-stimulating factor 2 (granulocyte-macrophage); CTL: cytotoxic T lymphocyte; ELISA: enzyme-linked immunosorbent assay; GFP: green fluorescent protein; GSEA: gene-set enrichment analysis; H-2Db: H-2 class I histocompatibility antigen, D-B alpha chain; H-2Kb: MHC class I H2-K-b; HIF1A: hypoxia-inducible factor 1 alpha; IFNG: interferon-gamma; IL: interleukin; ITGAX: integrin alpha X; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MHC: major histocompatibility complex; MTORC1: mammalian target of rapamycin kinase complex 1; PBS: phosphate-buffered saline; PFU: plaque-forming unit; RLR: retinoic acid-inducible-I-like receptor; ROS: reactive oxygen species; RPMI: Roswell Park Memorial Institute; RPS6KB1/S6K: ribosomal protein S6 kinase, polypeptide 1; RSV: respiratory syncytial virus; Th: T helper; TLR: toll-like receptor; Treg: regulatory T cells; UMAP: uniform manifold approximation and projection.

Dataset Information

Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer.

Publications

Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer.

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