Optimisation of immune effector function within the tumour microenvironment

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dc.contributor.advisor Tangney, Mark en
dc.contributor.author Byrne, William L.
dc.date.accessioned 2014-01-20T15:17:56Z
dc.date.issued 2013
dc.date.submitted 2013
dc.identifier.citation Byrne, W. L. 2013. Optimisation of immune effector function within the tumour microenvironment. PhD Thesis, University College Cork. en
dc.identifier.uri http://hdl.handle.net/10468/1309
dc.description.abstract Cancer represents a leading of cause of death in the developed world, inflicting tremendous suffering and plundering billions from health budgets. The traditional treatment approaches of surgery, radiotherapy and chemotherapy have achieved little in terms of cure for this deadly disease. Instead, life is prolonged for many, with dubious quality of life, only for disease to reappear with the inevitable fatal outcome. “Blue sky” thinking is required to tackle this disease and improve outcomes. The realisation and acceptance of the intrinsic role of the immune system in cancer pathogenesis, pathophysiology and treatment represented such a “blue sky” thought. Moreover, the embracement of immunotherapy, the concept of targeting immune cells rather than the tumour cells themselves, represents a paradigm shift in the approach to cancer therapy. The harnessing of immunotherapy demands radical and innovative therapeutic endeavours – endeavours such as gene and cell therapies and RNA interference, which two decades ago existed as mere concepts. This thesis straddles the frontiers of fundamental tumour immunobiology and novel therapeutic discovery, design and delivery. The work undertaken focused on two distinct immune cell populations known to undermine the immune response to cancer – suppressive T cells and macrophages. Novel RNAi mediators were designed, validated and incorporated into clinically relevant gene therapy vectors – involving a traditional lentiviral vector approach, and a novel bacterial vector strategy. Chapter 2 deals with the design of novel RNAi mediators against FOXP3 – a crucial regulator of the immunosuppressive regulatory T cell population. Two mediators were tested and validated. The superior mediator was taken forward as part of work in chapter 3. Chapter 3 deals with transposing the RNA sequence from chapter 2 into a DNA-based construct and subsequent incorporation into a lentiviral-based vector system. The lentiviral vector was shown to mediate gene delivery in vitro and functional RNAi was achieved against FOXP3. Proof of gene delivery was further confirmed in vivo in tumour-bearing animals. Chapter 4 focuses on a different immune cell population – tumour-associated macrophages. Non-invasive bacteria were explored as a specific means of delivering gene therapy to this phagocytic cell type. Proof of delivery was shown in vitro and in vivo. Moreover, in vivo delivery of a gene by this method achieved the desired immune response in terms of cytokine profile. Overall, the data presented here advance exploration within the field of cancer immunotherapy, introduce novel delivery and therapeutic strategies, and demonstrate pre-clinically the potential for such novel anti-cancer therapies. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013. William L Byrne en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject Gene therapy en
dc.subject RNA interference en
dc.subject Novel therapeutics en
dc.subject Tumour immunology en
dc.subject.lcsh Cancer--Gene therapy
dc.subject.lcsh Cancer--Immunotherapy en
dc.title Optimisation of immune effector function within the tumour microenvironment en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname MD en
dc.internal.availability Full text available en
dc.description.version Accepted Version
dc.contributor.funder Cork Cancer Research Centre, University College Cork en
dc.contributor.funder Health Research Board en
dc.description.status Not peer reviewed en
dc.internal.school Biochemistry en
dc.check.reason Releasing this thesis would cause substantial prejudice to the commercial interests of University College Cork en
dc.check.opt-out No en
dc.thesis.opt-out false
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat Both hard copy thesis and e-thesis en
ucc.workflow.supervisor m.tangney@ucc.ie
dc.internal.conferring Autumn Conferring 2013 en

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© 2013. William L Byrne Except where otherwise noted, this item's license is described as © 2013. William L Byrne
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