title: Transgene-derived overexpression of miR-17-92 in CD8+ T-cells confers enhanced cytotoxic activity.
abstract: MicroRNAs (miRs) play important roles in regulation of a variety of cell functions, including immune responses. We have previously demonstrated that miR-17-92 expression in T-cells enhances Th1 phenotype and provides a long-term protection against glioblastoma when co-expressed as a transgene in T-cells along with a chimeric antigen receptor. To further elucidate the function of miR-17-92 in tumor antigen-specific CD8(+) T-cells, we generated transgenic (Tg) mice in which CD8(+) T-cells overexpress transgene-derived miR-17-92 under the lck promoter as well as T-cell receptor specific for human gp10025-33 (Pmel-1) (miR-17-92/Pmel-Tg). CD8(+) T-cells from miR-17-92/Pmel-Tg mice demonstrated enhanced interferon (IFN)-γ production and cytotoxicity in response to the cognate antigen compared with those from control Pmel-Tg mice without the transgene for miR-17-92. In addition, miR-17-92/Pmel-Tg mouse-derived CD8(+)CD44(+) T-cells demonstrated increased frequencies of cells with memory phenotypes and IFN-γ production. We also found that miR-17-92/Pmel-Tg-derived CD8(+) T-cells expressed decreased levels of transforming growth factor (TGF)-β type II receptor (TGFBR2) on their surface, thereby resisting against suppressive effects of TGF-β1. Our findings suggest that engineering of tumor antigen-specific CD8(+) T-cells to express miR-17-92 may improve the potency of cancer immunotherapy.
authors: Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Brain Tumor, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors: Akemi
authors: A
authors: Kosaka
authors: Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Brain Tumor, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors: Takayuki
authors: T
authors: Ohkuri
authors: Department of Brain Tumor, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors: Maki
authors: M
authors: Ikeura
authors: Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Brain Tumor, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors: Gary
authors: G
authors: Kohanbash
authors: Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Brain Tumor, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Immunology Programs, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. Electronic address: hideho.okada@ucsf.edu.
authors: Hideho
authors: H
authors: Okada
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology*; D019076:Transgenes; D015854:Up-Regulation; D058951:gp100 Melanoma Antigen / Q000235:genetics
chemical_list: D018960:Hyaluronan Receptors; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; C548637:PMEL protein, human; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Antigen-specific CD8(+) T-cells; Cytotoxicity; IFN-γ; TGFBR2; miRNA-17-92