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

Hung-Chang Chen (1) , Noémie Joalland (2) , John S Bridgeman (1) , Fouad S Alchami (3) , Ulrich Jarry (2) , Mohd Wajid a Khan (1) , Luke Piggott (1, 4) , Yasmin Shanneik (1) , Jianqiang Li (5) , Marco J Herold (5, 6) , Thomas Herrmann (5) , David A Price (1, 7) , Awen M Gallimore (1, 7) , Richard W Clarkson (4, 8) , Emmanuel Scotet (2) , Bernhard Moser (1, 7) , Matthias Eberl (1, 7)

1 School of Medicine - Division of Infection and Immunity [Cardiff, UK]
2 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers
3 Cardiff and Vale University Health Board [Cardiff, UK]
4 School of Biosciences [Cardiff]
5 Institute for Virology and Immunobiology [Würzburg, Germany]
6 WEHI - The Walter and Eliza Hall Institute of Medical Research
7 Systems Immunity Research Institute [Cardiff, UK]
8 European Cancer Stem Cell Research Institute [Cardiff, UK]

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 CD44 hi CD24 lo 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 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.

Domaines: Cancer

Hung-Chang Chen, Noémie Joalland, John S Bridgeman, Fouad S Alchami, Ulrich Jarry, et al.. Synergistic targeting of breast cancer stem-like cells by human γδ T cells and CD8+ T cells. Immunology and Cell Biology, 2017, 95 (7), pp.620 - 629. ⟨10.1038/icb.2017.21⟩. ⟨inserm-01806851⟩