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Title: Fas Ligand and Tumour Immunology
Author: Newsom-Davis, Thomas Edmund
ISNI:       0000 0001 3444 314X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Fas ligand (FasL) is a transmembrane protein which induces apoptosis in cells expressing its receptor, Fas. The FasL/Fas pathway is one ofthe major mediators of cell death in the immune system but more recently an inflammatory role has been suggested. This thesis investigated the finding that when injected into mice, FasL-expressing (FasL+) tumours recruit a massive polymorphonuclear neutrophil (PMN) infiltration and are then rejected, which is followed by the development of antibody mediated tumour immunity. . In this work, eight IgM and one IgG2a monoclonal antibodies (mAbs) were produced from mice vaccinated with FasL+ murine melanoma. They recognised various syngeneic and allogeneic murine tumours cell lines. One mAb, TMIO, also recognised a range of human tumours cell lines but not untransformed cells. The epitopes of all the mAbs were carbohydrates expressed on proteins and/or lipids. The epitope of TMIO were high-mannose clusters on N-linked glycoproteins whilst another antibody, KM5.2, was recognising the glycolipid GM4. Both are novel tumour antigens. The IgG2a mAb had in vivp anti-tumour activity, protecting mice against the development ofboth cutaneous and metatstatic melanoma through antibody dependent cellular cytotoxicity. T~e mechanism behind the rejection and immunity to FasL+ tumours was studied using human cells. FasL promoted the production of chemokines by PMNs. PMNs, but not FasL, induced maturation of dendritic cells with a corresponding increase in T cell proliferation. FasL inhibited the generation of the THI subset ofCD4+ T cells, whereas PMNs promoted THI polansation and increased 1NFa and IL-22 production. -- , A model is proposed in which PMNs attracted to the tumour site promote rejection of FasL+ tumours by creating an inflammatory environment whilst recruiting and activating effector cells. They then induce antibody-mediated tumour immunity by facilitating the T cell help required. PMNs therefore act as a bridge between the innate and adaptive immune responses.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available