Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.702223
Title: Disabling factors mediating anti-tumour cytotoxic T lymphocyte suppression and tumour progression
Author: Basingab, Fatemah Salem
ISNI:       0000 0004 6056 8693
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2016
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Abstract:
Tumour cells are able to shape their microenvironment (TME) to promote further proliferation as well as promote immune suppression. Understanding the mechanisms of tumour-mediated immune suppression will enable the development of effective immunotherapies to combat cancer. Studies described in this thesis focus on understanding some of the mechanisms of suppressing anti-tumour CTL responses. We utilised BALB/c mouse renal carcinoma cells (Renca) expressing the haemagglutinin (HA) protein from influenza virus A/PR/8/H1N1 (PR8), as a model tumour antigen that can be recognised by KdHA-specific TcR transgenic CL4 CD8+ T cells. Renca-HA cells do not form metastatic tumours in vivo and so priming na'ive CL4 T cells to form CTLs relies upon cross presentation of KdHA epitopes by DCs to naive CL4 T cells within the tumour draining lymph nodes (TDLNs). However following priming, although CL4 CTLs can enter the tumour, they lose their CTL function and fail to control tumour growth. Our studies show that continuous growth of Renca-HA cells in vivo is associated with the presence of increased numbers of CD4+CD25+Foxp3+ and CD8+IFN-y+IL-10+ regulatory tumour-infiltrating T lymphocytes (TILs). The majority of these regulatory TILs also express the ectoenzymes: CD39 and CD73, which facilitate the production of adenosine within the TME. Critically, we show that antagonising adenosine receptors: A1, A2A, A28 and A3 on CL4 T cells protects them from the inhibitory effect of adenosine within the TME, by decreasing expression of immune checkpoint molecules: TIM-3 and TIGIT. In another study we show that when Renca-HA cells were made to overexpress COX-2 (Renca-T3 cells), the resulting overproduction of PGE2 caused them to metastasise to the TDLNs. However, despite this ability to metastasise, rather than enabling Renca-T3 cells to directly activate naive CL4 T cells to become CTLs, the overproduction of PGE2 actually inhibited the direct priming of tumour-specific CL4 CTLs by preventing the IFN-y-dependent up-regulation of ICAM-1, which is vital during the initial priming phase. Significantly, the addition of exogenous IFN-y was shown to act in a positive feedback manner, upregulating ICAM-1 expression by Renca-T3 cells, thus enhancing further IFN-y production, proliferation and CTL effector function amongst PGE2-treated CL4 T cells; which could prevent tumour growth in vivo. We also examined the role of B-cell lymphoma 3-encoded protein (BCL-3) in generating CL4 T cell responses. Data show that although COX-2/PGE2-overexpressing Renca-T3 cells upregulate BCL-3 expression, overexpression of BCL-3 by Renca-HA cells does not increase COX-2/PGE2 expression. However, BCL-3-overexpression does accelerate tumour growth in vivo, and this is associated with an increase in CD8+IFN-y+IL-10+TILs. Taken together these findings advocate that several different mechanisms exist to suppress the efficacy of anti-tumour CTL responses in vivo against metastatic and non-metastatic tumours, and that finding ways to block these pathways either separately or in combination will therefore help to control tumour growth.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.702223  DOI: Not available
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