Investigating the Role of\ud T-cells in Chronic Lymphocytic\ud Leukemia

Doctoral thesis English OPEN
Reed, Reiss
  • Subject: 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
  • References (60)
    60 references, page 1 of 6

    Chapter 5 Gene expression analysis of T-cells in CLL............................ 187 5.1 CD4+ T-cell analysis ..................................................................................................... 189 5.2 CD8+ T-cell analysis ..................................................................................................... 193 5.3 Discussion ...................................................................................................................... 196 5.4 Suggested further work ................................................................................................ 204 Jonker, D.J., O'Callaghan, C.J., Karapetis, C.S., Zalcberg, J.R., Tu, D., Au, H.-J., Berry, S.R., et al. 2007. Cetuximab for the Treatment of Colorectal Cancer. New England Journal of Medicine 357(20), pp. 2040-2048.

    1995. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373(6513), pp. 444-448.

    June, C.H. 2007. Adoptive T cell therapy for cancer in the clinic. The Journal of Clinical Investigation 117(6), pp. 1466-1476.

    Kaech, S.M. and Cui, W. 2012. Transcriptional control of effector and memory CD8+ T cell differentiation. Nature Reviews Immunology 12(11), pp. 749-761.

    Kalos, M., Levine, B.L., Porter, D.L., Katz, S., Grupp, S.A., Bagg, A. and June, C.H. 2011.

    T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Science Translational Medicine 3(95), p. 95ra73.

    Kantoff, P.W., Higano, C.S., Shore, N.D., Berger, E.R., Small, E.J., Penson, D.F., Redfern, Kaspar, A.A., Okada, S., Kumar, J., Poulain, F.R., Drouvalakis, K.A., Kelekar, A., Hanson, D.A., et al. 2001. A Distinct Pathway of Cell-Mediated Apoptosis Initiated by Granulysin.

    The Journal of Immunology 167(1), pp. 350-356.

    Kawakami, Y., Eliyahu, S., Jennings, C., Sakaguchi, K., Kang, X., Southwood, S., Robbins, P.F., et al. 1995. Recognition of multiple epitopes in the human melanoma antigen gp100 by tumor-infiltrating T lymphocytes associated with in vivo tumor regression. The Journal of Immunology 154(8), pp. 3961-3968.

    Keating, M.J., Flinn, I., Jain, V., Binet, J.-L., Hillmen, P., Byrd, J., Albitar, M., et al. 2002.

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