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Deep characterisation and functional analysis of CD4+ HLA-DR+ PD-1+ T cells in Chronic Lymphocytic Leukaemia

Henley, Peter 2021. Deep characterisation and functional analysis of CD4+ HLA-DR+ PD-1+ T cells in Chronic Lymphocytic Leukaemia. PhD Thesis, Cardiff University.
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Abstract

Chronic Lymphocytic Leukaemia (CLL) is the most common adult leukaemia in the Western world and is characterised by an accumulation of mature B cells in the circulation which can lead to hypogammaglobulinaemia and leaves patients highly susceptible to infections. There is currently no known cause for CLL, but there are considerable differences in its incidence: CLL is around twice as common in men as women, is rarely observed in Asian populations and has increasing prevalence with age, with a median age at diagnosis of 72 years. Despite being a cancer of B cells, CLL patients also show marked differences in the T cell compartment of the immune system. As well as changes in numbers and in the distribution of subsets, T cells in CLL often demonstrate widespread dysfunction including an impaired ability to form immune synapses. Whether the development of CLL leads to this T cell dysfunction, or whether T cell dysfunction precedes and permits the development of CLL, remains unclear. In this study, T cells from over 200 untreated, Stage A CLL patients were analysed in order to validate and build on previous work from our laboratory. That work identified CD4+ :CD8+ T cell ratio and the frequency of CD4+ HLA-DR+ PD-1+ T cells as potential prognostic factors in CLL. Here, flow cytometry, gene expression analysis and functional assays were used to validate the prognostic potential of these two T cell parameters and to explore the nature and function of the CD4+ HLA-DR+ PD-1+ T cell population. Using a larger cohort of CLL patients, this study confirmed that both CD4+ :CD8+ T cell ratio and the frequency of CD4+ HLA-DR+ PD-1+ T cells can be used to stratify patients, both in terms of progression-free survival and time to first treatment, with a similar prognostic power to other currently used CLL cell markers. Phenotyping of CD4+ HLA-DR+ PD-1+ T cells revealed this population to be highly heterogeneous, although there was a significant enrichment for markers of proliferation and cytotoxicity. Gene expression analysis conducted on CLL T cells revealed a strong association with exhaustion signalling, as well as changes to metabolic processes, while TOX was found to be the most significantly enriched gene in CD4+ HLA-DR+ PD-1+ T cells. However, no evidence of CLL T cell exhaustion was observed in cytokine production experiments and T cells expressing TOX appeared to have a greater proliferative response to stimulation in vitro. Overall, this study provides evidence that T cell parameters could represent valuable new prognostic markers in CLL. Although the exact role of CD4+ HLA-DR+ PD-1+ T cells remains unclear, it is evident that this population is abnormal. Further investigation into this T cell population could provide useful information about how this subset impacts CLL disease and inform future treatment strategies.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Last Modified: 19 May 2022 09:45
URI: https://orca.cardiff.ac.uk/id/eprint/149858

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