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Molecular and functional characterization of the role of Foxp3+ regulatory T (Treg) cells in the development of intestinal cancer

Prim Padilha, Ana 2018. Molecular and functional characterization of the role of Foxp3+ regulatory T (Treg) cells in the development of intestinal cancer. PhD Thesis, Cardiff University.
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Colorectal cancer (CRC) is one of the most common cancers in Europe and the fourth most common in the UK, being influenced by environmental factors, genetic mutations and interactions with the host immune system. The Wnt pathway plays a key role in maintaining intestinal homeostasis. Constitutive activation of Wnt occur in more than 80% of CRC, primarily due to the loss of the Apc gene. This mutation occurs in the intestinal stem cells (ISC), the cell of origin for CRC. ISCs are identified by Lgr5 expression. The immune microenvironment of these tumours plays a key role in their progression. The local recruitment of immunosuppressive Foxp3+ regulatory T-cells (Tregs) has been demonstrated in CRC patients, however it is unclear whether they limit or promote the anti-tumour immune responses. Importantly most of the studies were done in patients with advanced disease, highlighting the need to understand the role of these cells in the early stages of tumourigenesis. To understand the influence of Tregs on an ISC following an oncogenic mutation, genetically modified mice were used. Using the Lgr5 transgene, to conditionally delete Apc in the intestinal stem cell (ISC), it is possible to model the initial stages of CRC. This mouse was crossed with the Foxp3DTR mouse, which expresses the human diphtheria toxin receptor under the control of the Foxp3 promotor (Lgr5CreERT2Apcfl/flFoxp3DTR). Selective depletion of Tregs can be achieved by injection of diphtheria toxin, enabling the investigation of the role that Tregs and conventional T-cells play during malignant transformation. To identify the role of other immune cell populations in the anti-tumoral immune response, CD4+ and CD8+ cells were depleted and IFNγ was neutralized in the Lgr5CreERT2Apcfl/flFoxp3DTR mouse model. Here, it was shown that 15 days following Apc deletion, the number of Tregs increased in the small and large intestines, spleen and mesenteric lymph nodes (MLN). Treg depletion, in Apc deleted mice, resulted in a reduction of the intestinal tumour burden. The same was observed in mice where CD4+ and CD8+ cells were depleted. IFNγ neutralization had no effects. In this mouse model, data suggest that CD4+, CD8+ cells or IFNγ do not play a role in the anti-tumour immune responses. Overall these data indicate that Tregs inhibit the immune recognition of newly transformed ISCs suggesting that Tregs play a key role in the early stages of intestinal cancer by promoting tumourigenesis. This is particularly important as Tregs can be a possible target in the early stages of CRC and their modulation might prevent tumour progression, improving the outcome of CRC patients.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > Q Science (General)
Funders: Cancer Research UK
Date of First Compliant Deposit: 1 March 2019
Last Modified: 10 Mar 2020 02:40

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