title: Synergistic targeting of breast cancer stem-like cells by human γδ T cells and CD8+T cells.
abstract: The inherent resistance of cancer stem cells (CSCs) to existing therapies has largely hampered the development of effective treatments for advanced malignancy. To help develop novel immunotherapy approaches that efficiently target CSCs, an experimental model allowing reliable distinction of CSCs and non-CSCs was set up to study their interaction with non-MHC-restricted γδ T cells and antigen-specific CD8+T cells. Stable lines with characteristics of breast CSC-like cells were generated from ras-transformed human mammary epithelial (HMLER) cells as confirmed by their CD44hiCD24loGD2+phenotype, their mesenchymal morphology in culture and their capacity to form mammospheres under non-adherent conditions, as well as their potent tumorigenicity, self-renewal and differentiation in xenografted mice. The resistance of CSC-like cells to γδ T cells could be overcome by inhibition of farnesyl pyrophosphate synthase (FPPS) through pretreatment with zoledronate or with FPPS-targeting short hairpin RNA. γδ T cells induced upregulation of MHC class I and CD54/ICAM-1 on CSC-like cells and thereby increased the susceptibility to antigen-specific killing by CD8+T cells. Alternatively, γδ T-cell responses could be specifically directed against CSC-like cells using the humanised anti-GD2 monoclonal antibody hu14.18K322A. Our findings identify a powerful synergism between MHC-restricted and non-MHC-restricted T cells in the eradication of cancer cells including breast CSCs. Our research suggests that novel immunotherapies may benefit from a two-pronged approach combining γδ T-cell and CD8+T-cell targeting strategies that triggers effective innate-like and tumour-specific adaptive responses.
authors.affiliation: Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Hung-Chang
authors.initials: HC
authors.lastname: Chen
authors.affiliation: INSERM, Unité Mixte de Recherche 892, Centre de Recherche en Cancérologie Nantes Angers, Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.|Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 6299, Nantes, France.
authors.forename: Noémie
authors.initials: N
authors.lastname: Joalland
authors.affiliation: Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: John S
authors.initials: JS
authors.lastname: Bridgeman
authors.affiliation: Cardiff and Vale University Health Board, University Hospital of Wales, Cardiff, UK.
authors.forename: Fouad S
authors.initials: FS
authors.lastname: Alchami
authors.affiliation: INSERM, Unité Mixte de Recherche 892, Centre de Recherche en Cancérologie Nantes Angers, Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.|Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 6299, Nantes, France.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jarry
authors.affiliation: Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Mohd Wajid A
authors.initials: MWA
authors.lastname: Khan
authors.affiliation: Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.|School of Biosciences, Cardiff University, Cardiff, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Piggott
authors.affiliation: Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Shanneik
authors.affiliation: Institute for Virology and Immunobiology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute for Virology and Immunobiology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.|Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.affiliation: Institute for Virology and Immunobiology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Herrmann
authors.affiliation: Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.|Systems Immunity Research Institute, Cardiff University, Cardiff, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.|Systems Immunity Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Awen M
authors.initials: AM
authors.lastname: Gallimore
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, UK.|European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Clarkson
authors.affiliation: INSERM, Unité Mixte de Recherche 892, Centre de Recherche en Cancérologie Nantes Angers, Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.|Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 6299, Nantes, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Scotet
authors.affiliation: Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.|Systems Immunity Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Moser
authors.affiliation: Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.|Systems Immunity Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Matthias
authors.identifier: 0000-0002-9390-5348
authors.initials: M
authors.lastname: Eberl
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D004164:Diphosphonates / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D008285:Major Histocompatibility Complex; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D000077211:Zoledronic Acid; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000906:Antibodies; D004164:Diphosphonates; D000939:Epitopes; D007093:Imidazoles; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077211:Zoledronic Acid; D007371:Interferon-gamma; D018631:ras Proteins