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Title: Human γδ T cell-based immunotherapy for breast cancer
Author: Chen, Hung-Chang
ISNI:       0000 0004 5919 6562
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2015
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Scientific background. The inherent resistance of breast cancer stem cells (CSCs) to existing therapies has largely hampered effective treatments for advanced breast cancer. My research aimed at establishing novel immunotherapy approaches efficiently targeting CSCs by harnessing human γδ T cells as non-MHC-restricted killer cells and simultaneously as APCs to induce tumour-specific CD8+ T cell responses. Approach. An experimental model allowing reliable distinction of CSCs and non-CSCs was set up to study their interaction with γδ T cells and CD8+ T cells. FluM1 and CMVpp65 viral epitopes were used as surrogates for yet-to-be-discovered CSC-associated antigens. Results. Stable sublines with characteristics of CSCs and non-CSCs were generated from ras-transformed human mammary epithelial (HMLER) cells as confirmed by their (i) distinct expression profiles of CD24, CD44 and GD2, (ii) mesenchymal- and epitheliallike characteristics, (iii) differential growth patterns in mammosphere culture and (iv) distinct tumourigenicity, self-renewal and differentiation in NSG mice. The resistance of both CSCs and non-CSCs to γδ T cells could be overcome by inhibition of FPPS through pretreatment with zoledronate or FPPS-targeting shRNA, resulting in increased cytotoxicity and APC function of γδ T cells. CSCs presenting FluM1 or CMVpp65 exhibited stronger resistance to antigen-specific CD8+ T cells as compared to their non-CSC counterparts. Of note, pretreatment of Flu M1- or CMVpp65-presenting CSCs with γδ T cell conditioned supernatant significantly increased surface expression of MHC class I and ICAM-1 by both CSCs and non-CSCs as well as their susceptibility to CD8+ T cellmediated killing. Moreover, using the humanised anti-GD2 monoclonal antibody,Hu14.18K322A, a specific direction of γδ T cell responses against CSCs could be achieved. In addition to their direct cytotoxicity and ability to modulate the susceptibility of CSCs and non-CSCs to CD8+ T cell-mediated killing, γδ T cells concomitantly functioned as APCs to initiate de novo tumour-specific cytotoxic CD8+ T cell responses. Conclusions. My findings identify a powerful synergism between MHC-restricted and non-MHC-restricted T cells in the eradication of both CSCs and non-CSCs, thus establishing a powerful positive feedback loop for the eradication of residual cancer cells survived from killing by γδ T cells. My 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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)