In recent years, substantial evidence has been generated demonstrating the importance of the immune system in preventing and controlling the growth of many cancers, including colorectal adenocarcinomas. In particular, populations of tumour-specific effector T cells appear to play a crucial role in restricting the generation and expansion of transformed neoplastic cells. However, the fact that tumours continue to grow in the presence of a seemingly intact immune system suggests that these responses are often inadequate. CD4+Foxp3+ T regulatory cells (Tregs) have been shown to play a key role in modulating the immune system by keeping immune responses to self-antigens in check, thereby preventing autoimmunity. These cells also appear to be employed by tumours to protect against recognition and eradication, and have been demonstrated to impinge upon the anti-tumour immune response in humans. Furthermore, it appears that the tumour microenvironment facilitates the development of highly immunosuppressive T cells, which may also allow subsequent tumour progression. In colorectal cancer, the relationship between Tregs and tumour progression is less clear – despite their well-documented ability to impinge on anti-tumour immune responses, increased tumour infiltrates have also been associated with prolonged survival. In this thesis, the phenotype and function of CD4+ T cells derived from PBMC, colon and tumour samples were analysed for suppressive markers by FACS, and anti-tumour responses by IFN-γ ELISpot. CRC patients with more advanced tumours responded to fewer epitopes and generated a significantly weaker epitopespecific T cell response to the oncofoetal antigen, 5T4 than healthy donors. Human depletion experiments both in vitro and in vivo indicated suppression by Foxp3+ regulatory CD4+ T cells. These cells were found in abundance amongst tumourinfiltrating lymphocytes; however, another equally prominent population of IL-10 and TGF-β-producing CD4+Foxp3- T cells were found to be >50-fold more suppressive. Thus, a major caveat to cancer immunotherapy is the suppressive tumour microenvironment, which contributes to the selective decline of measurable antitumour CD4+ T cell responses as tumours progress. These responses were enhanced in metastatic CRC patients by depleting regulatory T cells. It is hoped such findings will augment our understanding of how anti-tumour CD4+ T cells are activated and conversely regulated, with the intention of designing better treatment for patients with colorectal cancer.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:571750 |
| Date | January 2013 |
| Creators | Scurr, Martin John |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/47419/ |
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