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Mechanisms of Foxp3+ Regulatory T cell enrichment and High Endothelial Venule formation in tumours

Colbeck, Emily 2015. Mechanisms of Foxp3+ Regulatory T cell enrichment and High Endothelial Venule formation in tumours. PhD Thesis, Cardiff University.
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Abstract

Foxp3+ Regulatory T cells (Tregs) constitute a major immunosuppressive cell type within tumours. Here, they impinge on anti-tumour immune responses. Modalities aimed at subverting the accumulation and / or suppressive action of Tregs could revolutionise cancer immunotherapies in the future. By use of the 3-methylcholanthrene (MCA) model of chemical carcinogenesis, I investigated mechanisms of Treg enrichment in tumours. While a large proportion of intra-tumoural Tregs expressed the TH1 transcription factor, T-bet, there was no role for T-bet-expressing Tregs in tumour control. Additionally, sequestration of Interleukin-2 (IL-2) in the tumour microenvironment (TME) did not represent a mechanism by which Tregs exert dominance at this site. However, the majority of intra-tumoural Tregs expressed CD69, a molecule implicated in retaining T cells at the site of antigen. Furthermore, CD69-expressing Tregs possessed superior suppressive capacity relative to CD69 negative Tregs. Therefore, the consequence of CD69 expression on Tregs may be the retention of tumour-infiltrating super-suppressive Tregs, thereby ensuring Treg dominance within the TME. By use of the Foxp3DTR mouse model, previous data demonstrated the development of ectopic High Endothelial Venules (HEV) within MCA-induced tumours following depletion of Treg. HEV demonstrated an absolute concordance with increased numbers of T cells inside tumours and reduced tumour growth. I investigated the mechanisms supporting development of HEV in tumours in the absence of Tregs. I have eliminated a role for B lymphocytes, instead pinpointing CD8+ T cells as key drivers of HEV development in tumours. Ectopic formation of HEV in Treg depleted tumours is Tumour Necrosis Factor (TNF) receptor (TNFR) signalling dependent, and Lymphotoxin (LT) β receptor (LTβR) signalling independent. Furthermore, the proportion of TNFα-producing T cells in the tumour correlated with density of tumour HEV. These data suggest that intra-tumoural development of HEV following Treg depletion is driven by T cell derived TNFα signalling via TNFR(s).

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Funders: Cancer Research UK
Date of First Compliant Deposit: 30 March 2016
Last Modified: 12 Jan 2017 02:30
URI: http://orca-mwe.cf.ac.uk/id/eprint/84794

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