Contribution of tumour cell signalling and the microenvironment to the pathogenesis of EBV-associated B cell lymphoma and

Ibrahim, Maha (2018). Contribution of tumour cell signalling and the microenvironment to the pathogenesis of EBV-associated B cell lymphoma and. University of Birmingham. Ph.D.

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Abstract

In this thesis I have explored different components of the pathogenesis of several related EBV associated cancers. In the first part of the thesis I focus on the microenvironment of two of these cancers, nasopharyngeal carcinoma (NPC) and diffuse large B cell lymphoma (DLBCL). Our group has developed a therapeutic vaccine against EBV which has already been shown to be safe in patients with NPC. Therefore, in the first results chapter (chapter 3), I present a description of the phenotyping of expression of the immune microenvironment including immune checkpoint (ICP) genes and MHC class I and class II genes in NPC tissues. I showed for the first time in NPC tissue samples, two types of PD-L1 expressing tumours: diffuse and marginal. In re-analysis of published data, I found co-expression of immune checkpoint genes and their receptors in EBV positive NPC samples; information which is likely to inform the design of combination immunotherapy in NPC patients. I have shown in my re-analysis of EBV positive NPC that PD-L1 is not up-regulated by LMP-1. In chapter 4, I show the results of studies of the expression of collagen and collagen receptors in DLBCL in which I have identified the over-expression of a potentially novel immune checkpoint receptor, LAIR-1, on the macrophages infiltrating this tumour. In the second part of the thesis I switch my line of inquiry to the tumour cells of EBV-associated cancers, this time focussing on Hodgkin lymphoma (HL), another EBV-associated lymphoma. During the course of the work presented in this chapter I was able to define a role for aberrant sphingosine-1-phosphate (S1P) signalling in driving PI3-K activation mediated through up-regulation of S1PR1 and downregulation of S1PR2 receptors in HL. I also showed that in turn, PI3-K signalling increases the expression of potentially oncogenic downstream transcription factors, such as BATF3 which I have shown to be overexpressed in HL. These data suggest that antagonists of S1P could be considered for the treatment of patients with HL.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Supervisor(s):
Supervisor(s)EmailORCID
Murray, PaulUNSPECIFIEDUNSPECIFIED
Wei, WenbinUNSPECIFIEDUNSPECIFIED
Licence:
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Cancer and Genomic Sciences
Funders: Other
Other Funders: Ministry of Higher Education and Scientific Research, Egypt, South Egypt Cancer Institute, Assiut University, Egypt
Subjects: R Medicine > RB Pathology
URI: http://etheses.bham.ac.uk/id/eprint/8099

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