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Synergistic targeting of breast cancer stem-like cells by human γδ T cells and CD8+ T cells

Chen, Hung-Chang, Joalland, Noémie, Bridgeman, John S, Alchami, Fouad S, Jarry, Ulrich, Khan, Mohd Wajid A, Piggott, Luke, Shanneik, Yasmin, Li, Jianqiang, Herold, Marco J, Herrmann, Thomas, Price, David A., Gallimore, Awen M., Clarkson, Richard W., Scotet, Emmanuel, Moser, Bernhard and Eberl, Matthias 2017. Synergistic targeting of breast cancer stem-like cells by human γδ T cells and CD8+ T cells. Immunology and Cell Biology 95 (7) , pp. 620-629. 10.1038/icb.2017.21

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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 CD44hi CD24lo GD2+ 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 shRNA. 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Medicine
Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: Nature Publishing Group
ISSN: 0818-9641
Funders: Cancer Research UK, Cancer Research UK, Wellcome Trust
Date of First Compliant Deposit: 30 March 2017
Date of Acceptance: 24 March 2017
Last Modified: 25 Feb 2019 00:03
URI: http://orca.cf.ac.uk/id/eprint/99538

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