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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Reed, Reiss
Languages: English
Types: Doctoral thesis
Subjects: R1
T-cells appear to have multiple conflicting roles in CLL. On the one hand tumour-specific T-cells could be used to deliver effective immunotherapy; on the other hand, certain T-cell populations may enhance CLL survival and disease progression. The aim of this thesis was to address these contradictory aspects and to provide a deeper understanding of the role of T-cells in CLL.\ud Firstly, candidate peptides from the pro-apoptotic protein Bax were used to activate potential CLL specific T-cells from HLA-A2+ patients. A CD8+ T-cell clone (6C5) was isolated and it’s specificity was initially mapped to (Bax161-170; LLSYFGTPT) and(Bax160–170; GLLSYFGTPT). However, 6C5 failed to recognise HLA-A2+ CLL cells in vitro,\ud and failed to recognise highly purified forms of the peptides. Further characterisation, involving mass spectrometry and HPLC, mapped T-cell specificity to a modified peptide (LLSY(3-tBu)FGTPT). A second strand of this project involved detailed phenotypic analysis of T-cells from CLL patients (n=97) in order to investigate the basis for immune dysfunction. This analysis indicated that patients with an inverted CD4:CD8 ratio (CLLIR), displayed a\ud skewing towards a highly differentiated T-cell phenotype, as well as expression of markers associated with replicative senescence (CD57+, CD27-) within CD4+ and CD8+ T-cell compartments. In addition, CD4+ T-cells expressing markers associated with immunosuppression (PD-1+, TIM-3+) were also increased in CLLIR. Importantly, the\ud inversion of the CD4:CD8 ratio was associated with shorter progression-free survival.\ud Furthermore, the frequencies of distinct T-cell populations were also shown to haveprognostic impact in both univariate analysis (CD4+PD-1+, CD4+CD57+, CD8+CD57+ and\ud CD8+CD27-) and multivariate analysis (CD4+CD27-PD-1+LAG-3+ and CD8+CD27- CD57+PD-1+).\ud To further evaluate the differences between CLLIR and CLLNR patients, preliminary transcriptional analysis was performed, focusing on genes associated with T-cell function.\ud By contrast, transcriptional analysis suggested that genes associated with activation rather\ud than suppression were enriched in CLLIR
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