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Title: Elucidating the role of regulatory T cells in colorectal cancer progression
Author: Besneux, Matthieu
ISNI:       0000 0004 5372 2154
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2015
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Antigens (Ags) expressed by cancer cells can be specifically recognised by T cells contributing to anti-tumour immunity. For this reason, tumour Ag-specific T helper type 1 (Th1) cells can be detected in cancers and their infiltration is predictive of a prolonged disease-free survival. However, their activity is suppressed by T cells with inhibitory functions i.e. regulatory T cells (Tregs). High infiltration of tumours by these cells often correlates with poor survival. It is therefore crucial to understand their activity. Since Th1 and Treg cells are activated after Ag recognition, it is plausible that tumour Ag-specific Tregs inhibit Th1-mediated tumour immunity. Furthermore, vaccination, rather than inducing effector T cells, may be detrimental by activating Tregs. Increased numbers of CD25hi Treg cells are found in cancer patients, including CRC. However, in contrast to many cancers, the phenotype of these cells has not been studied in CRC patients. In this thesis, phenotypes of circulating, colon and tumour infiltrating Tregs are described. A high percentage of intratumoural CD4+CD25hi Tregs was found to express immunosuppressive molecules and these cells were enriched in late-stage CRC tumours. In addition, this thesis describes the measurement of Th1 and Treg cells recognising the oncofetal Ag, 5T4. Four immunogenic regions within the oncofoetal tumour Ag 5T4 and 14 peptides able to bind to most commonly found human HLA-DR alleles were identified. CD4+CD25hi cells mediated the control of tumour Ag 5T4-specific Th1 responses in CRC patients and their suppressive activity was not restricted to Th1 cells of the same Ag specificity. Also, responses to some, but importantly not all, immunogenic helper peptides discovered were influenced by Tregs. Thus Tregs may contribute to CRC progression by influencing tumour Ag- specific responses of Th1 cells. This body of work brings more information regarding the tumour Ag-specificity of Tregs and offers a future rationale to design peptide-based vaccines which exclude Treg peptides.
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)