AbstractLymphotoxin Beta Receptor (LTβR) and Herpes Virus Entry Mediator (HVEM), known as the lymphotoxin receptors, are non-death domain containing members of the TNFR family that can be activated through a complex net of ligands and ligand complexes. Activation of the lymphotoxin receptors can result in a number of different functional outcomes, including proliferation, differentiation, inflammation and apoptosis. Inconsistencies in existing literature have created some conflicting views regarding activation, signalling, functional outcome and relative importance of each receptor. Previous work in our research team which had utilised well characterised cell models to investigate the activation of the lymphotoxin receptors using various forms of the ligand whose full name is: homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes (LIGHT). Membrane presented LIGHT (mLIGHT), soluble agonists and recombinant ligands have previously been used. This thesis investigated the effects of mLIGHT and the novel Hexavalent agonist, HERA-LIGHT, in renal cell carcinoma (RCC) cell lines. HERA-ligands have been designed to overcome the need for secondary cross-linking via Fcγ receptors and, therefore, bridge the gap between soluble monoclonal anti-body (mAb) agonists and the superior membrane presented signals.
This thesis demonstrated the ability of mLIGHT to induce, albeit at varying degrees, in RCC cell lines. Moreover, for the first time, it was shown that a HERA-Ligand (in this case HERALIGHT) was able to directly induce cell death through lymphotoxin receptor activation. However, it was demonstrated that mLIGHT still induced greater levels of cell death than HERA-LIGHT.
This thesis has given a valuable insight into the effect of lymphotoxin receptor activation on RCC cell lines and initiated a number of avenues of further research that will contribute to the greater understanding of the lymphotoxin system.
|Date of Award||2023|
|Supervisor||Nik Georgopoulos (Main Supervisor) & Khalidah Ibraheem (Co-Supervisor)|