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

Hung‐Chang Chen,Yasmin Shanneik,Richard W Clarkson,David A Price,Mohd Wajid A Khan,Ulrich Jarry,Luke Piggott,Jianqiang Li,Awen M Gallimore,Fouad S Alchami,Bernhard Moser,Matthias Eberl,Noémie Joalland,Emmanuel Scotet,Thomas Herrmann,Marco J Herold,John S Bridgeman

doi:10.1038/icb.2017.21

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 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.

Highlights

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Immortalised human mammary epithelial cells transformed by overexpression of human telomerase reverse transcriptase, SV40 large T antigen and oncogenic ras[18] showed a predominant CD44lo CD24hi phenotype under adherent culture conditions, yet contained a distinct and stable population of CD44hi CD24lo cells that comprised 0.4–2% of all cells (Figure 1a).[3]
The phenotype and morphology of CD44lo CD24hi non-cancer stem cells (CSCs) was consistent with epithelial characteristics, while CD44hi CD24lo CSC-like cells showed signs of an incomplete epithelial-to-mesenchymal transition (EMT) with predominantly mesenchymal characteristics

Summary

Introduction

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. Cancer stem cells (CSCs) are the principal cause of disease recurrence, distant metastasis, and eventually morbidity and mortality in patients with different malignancies, including breast cancer.[1] The inherent resistance of CSCs to existing therapies has largely hampered the development of effective treatments for patients with advanced disease, and there is a paucity of studies aiming at directly targeting the CSC pool.[2] While CSCs are very rare cells and challenging to work with, in particular in humans, progress has been made by linking the cellular epithelial-to-mesenchymal transition (EMT) programme to the generation of CSC-like cells, especially in breast cancer.[3] In this respect, immortalised human mammary epithelial cells undergoing EMT acquire CSC properties, as judged by their CD44hi CD24lo phenotype, their ability to form mammospheres and their tumour initiation potential.[3,4,5]. Immunotherapy offers novel and potentially effective routes to treating cancer, and progress has been made with regard to adoptively transferring expanded or genetically engineered T cells back into patients.[6,7] the safety and efficacy of CD8+

Methods

Results

Conclusion