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Evaluating how auto-reactive T cells promote the progression of colorectal cancer

Thomson, Amanda Ann 2018. Evaluating how auto-reactive T cells promote the progression of colorectal cancer. PhD Thesis, Cardiff University.
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Abstract

Substantial evidence has been generated demonstrating that the immune system is important for controlling tumour development. This includes colorectal cancer (CRC). Current dogma states that patients capable of mounting anti-tumour immune responses have increased survival. As a result, therapies to enhance antitumour immune responses are an attractive treatment strategy for cancer patients. However, the long-term effect of generating such responses is not fully understood. Our laboratory has previously shown that an IFN-γ response towards the tumour antigen Carcinoembryonic antigen (CEA) is associated with tumour recurrence in CRC patients. In contrast, a 5T4 IFN-γ response provided a protective advantage. In this thesis, reasons to explain this observation were explored. Firstly, anti-CEA IL-17A and dual IFN-γ/IL-17A responses were investigated to determine if high frequencies of IL-17A could potentially outweigh a beneficial IFN-γ response. Infiltration of CD4+ T cell subsets into tumours from CEA responding and non-responding patients was also examined. Results revealed that CEA specific IL-17A responses were not up-regulated in CRC patients compared to healthy donors, nor were they increased compared to IL-17A 5T4 specific responses. IL-17A+ CD4+ T cell infiltration was also not increased within patients harbouring a CEA T cell response. However, infiltration of other T helper subsets was reduced. These data imply that IL-17A release is not responsible for early tumour recurrence. Results also suggest that tumours developing within CEA responding patients may be less immunogenic and hence more aggressive. Investigations were also made to assess if a blood CEA T cell response was associated with increased intestinal permeability. Data obtained via Using chamber experiments suggests that a high magnitude CEA response is associated with reduced gut integrity in the right side of the colon. Further experiments are required, but it is possible that increased permeability could allow translocation of microbial products, leading to an inflammatory environment that could aid tumour development. It’s hoped that such findings will help to explain the potential long-term effects of generating anti-tumour immune responses. This knowledge would be beneficial when selecting targets for immunotherapy.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Medicine
Last Modified: 14 Jan 2019 10:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/118291

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