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dc.contributor.authorMcClanahan, Fabienne
dc.date.accessioned2015-09-21T09:52:34Z
dc.date.available2015-09-21T09:52:34Z
dc.date.issued2015-02-13
dc.identifier.citationMcClanahan, F. 2015. Investigating and reversing T-cell dysfunction in the Eμ-TCL1 mouse model of chronic lymphocytic leukaemia (CLL). Queen Mary University of Londonen_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/8761
dc.descriptionPhDen_US
dc.description.abstractChronic lymphocytic leukaemia (CLL) is the most common adult leukaemia, and despite recent introduction of targeted therapies, remains incurable. An important hallmark of CLL is severe immune deficiency, including the failure to mount effective anti-tumour immune responses. This can partly be explained by insufficient antigen presentation, but also by the existence of complex CLL-induced T-cell defects. Based on the cancer immuno-editing hypothesis that the immune system not only protects a host against tumour formation but can also be compromised to actively provide a pro-tumour microenvironment, modulating cancer-induced T-cell defects could restore the full anti-tumour response and result in more durable clinical responses. The immune checkpoint molecules PD-1 (expressed on activated immune effector cells) and PD-L1 (expressed on antigen-presenting and microenvironmental cells including tumour cells) have emerged as important mediators of T-cell suppression. Several studies suggest that PD-L1/PD-1 inhibitory signalling in CLL might be overcome by the immune modulatory drug lenalidomide. Furthermore, directly targeting PDL-1/PD-1 interactions produces significant responses in solid cancers. However, similar studies are notably absent in CLL, and the effect of PDL-1/PD-1 blockade on restoring cancer-induced immune dysfunction is not understood. Transgenic Eμ-TCL1 mice have been extensively validated as an adequate preclinical model of aggressive human CLL, and our group showed their suitability to mirror T-cell defects observed in human CLL. Using the Eμ-TCL1 model, this dissertation project substantially extends our previous characterization of CLL-induced T-cell dysfunction and evaluates the functional impact of PD-L1/PD-1 inhibitory signalling both in parallel with disease development and in different microenvironments. The findings to be described here demonstrate that developing CLL is associated with specific T-cell subset alterations, phenotypic changes, and functional defects that are very similar in peripheral blood and secondary lymphoid organs. In addition to PD-L1, PD-L2 is identified as a potential mediator of inhibitory signalling in CLL. CD8+ T cells in leukaemic mice are characterised as a functionally heterogeneous population, in which subsets of cells are able to exert effector functions despite PD-1 expression. In vivo lenalidomide treatment repairs selected phenotypic alterations and immune synapse formation, and a PD-L1 IgG blocking antibody effectively controls disease and reverses global T-cell defects even in cells expressing PD-1. In sum, this work provides a strong rationale to explore PD-L1/PD-1 targeting in CLL clinical trials, potentially in combination with novel agents.en_US
dc.description.sponsorshipMildred-Scheel Postdoctoral Fellowship awarded by Deutsche Krebshilfe (salary 2011-2013), by the Virtual Helmholtz Institute “VH404 - Resistance in Leukaemia” (salary and consumables, 2013-2015), and by the Kenneth Street Endowment Fund (consumables, 2011-2015).en_US
dc.language.isoenen_US
dc.publisherQueen Mary University of Londonen_US
dc.subjectCanceren_US
dc.subjectchronic lymphocytic leukaemiaen_US
dc.subjectT-cell defects.en_US
dc.titleInvestigating and reversing T-cell dysfunction in the Eμ-TCL1 mouse model of chronic lymphocytic leukaemia (CLL)en_US
dc.typeThesisen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author


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