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The role of CD200 in kidney cancer immune evasion

Davies, Gemma 2023. The role of CD200 in kidney cancer immune evasion. PhD Thesis, Cardiff University.
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Summary Kidney cancer is the 7th most common cancer type in the UK, with around 13,300 new cases diagnosed every year, accounting for 4% of new cancer cases and 3% of all cancer deaths. Renal cell carcinoma (RCC) is the most common form of kidney cancer, of which clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype, making up around 75% of cases. All RCC is resistant to chemotherapy and radiotherapy, so surgery is the gold standard treatment for early-stage disease. Late-stage disease however has limited treatment options, with poor response rates and high risk of relapse observed with immunotherapy. Therefore, new immune checkpoint therapeutic targets are urgently required. Engagement of CD200 with its receptor is an immunosuppressive immune checkpoint which is overexpressed in several cancer types, enabling immune evasion and disease progression. CD200 is subject to ectodomain shedding, creating a functionally active soluble form known as sCD200. In this thesis, we characterise CD200 expression in normal kidney and RCC tissue, then examine its relationship firstly with proteases to establish their role in CD200 ectodomain shedding, and secondly with tumour-infiltrating immune cells to determine its effect on the anti-tumour immune response. We examined expression of ADAM9, ADAM17 and ADAM28 in combination with CD200, with high numbers of double positive cells present throughout ccRCC tumour tissue. ADAM9 was found to have a novel role in CD200 ectodomain shedding, resulting in a dosedependent increase in sCD200 presence in our cell line experiments. CD200 expression was found to significantly alter RCC immune infiltrate compared to normal kidney, and we characterised a ccRCC-specific ‘high effector T cell’ immune signature which was associated with poor prognosis. Finally, we showed that both CD200 and sCD200 are able to protect tumour cells against NK cell-mediated cytotoxic activity. Taken together, this data shows that blockade of CD200 may be a potential therapeutic option for RCC patients.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > Q Science (General)
Funders: KESS2
Date of First Compliant Deposit: 18 October 2023
Last Modified: 18 Oct 2023 09:50

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