Angell, Helen K.
(2012)
Immune modulation of the tumour microenvironment.
PhD thesis, University of Nottingham.
Abstract
Regulatory T cells (Tregs) are a distinct lymphocyte lineage, functionally defined as T cells that inhibit an immune response, which is crucial for maintaining peripheral tolerance and the prevention of autoimmunity. Tregs have been implicated in tumour immune evasion, suppressing the anti-tumour immune response, resulting in tumour progression. The aim of this PhD was to recognise how Tregs function and understand how they are able to modulate tumour immunology. In order to research their proposed role in cancer, it was necessary to be able to phenotype, sort and expand functional Tregs. In preliminary research, strategies were designed to phenotype and test the functionality of ex vivo Tregs and commercial isolation kits were tested and compared in terms of cost efficiency and effectiveness. The mechanisms of Treg-mediated suppression were investigated, including the necessity for cell-to-cell contact and the involvement of key cytokines. The importance of particular cytokines in Treg-mediated suppression was not clear; but cell contact appears to be required for optimal suppression.
The project then aimed to address whether or not the importance of Tregs highlighted in the literature was reflected in a clinical setting. The significance of immune cell orientation within the tumour microenvironment was researched, investigating the co- localisation between key immune cell subtypes and their correlation with areas of tumour proliferation, apoptosis, hypoxia and vasculature coverage. In order to achieve this successfully, immunohistochemical techniques were optimised and image analysis algorithms were constructed to facilitate rigorous and systematic quantification of immune cell infiltrates in primary colorectal and metastatic liver cancer patients. Significant increases in the prevalence of Tregs, CD8 cells, macrophages and natural killer (NK) cells were observed within the stroma, compared with the tumour. A metastatic phenotype was alluded to; encompassing elevated Tregs and reduced numbers of CD8 cells.
Further to this, the level of Tregs in the peripheral blood and tumour tissue of liver- metastatic patients were assessed to investigate whether any correlation existed between circulating and tumour-infiltrating Tregs. It was shown that within peripheral blood, patients exhibited a TreghighCD8lowNKlow phenotype, when compared with healthy volunteers.
Finally, the project aimed to build an in vitro human Treg tumour-killing suppression model to examine the ability of Tregs to inhibit NK cell-mediated cytotoxicity. The mechanism for this was investigated, evaluating the importance of the NK group 2 member D (NKG2D) receptor ligand interaction, to mediate cell killing in a transforming growth factor-β dependent manner.
This study adds to the ongoing discussion on the role of immune cells in metastatic development. Accumulating evidence points to a critical role of immune infiltrates in allowing metastatic development, where Tregs support tumour growth by suppressing the host anti-tumour immune response.
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