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Title: Tumour-specific CTLs : what does it take to wake them up?
Author: Yafei, Zain Al
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2012
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The immunosurveillance hypothesis states that the immune system recognises and responds to tumours preventing growth and progression and that tumour- infiltrating CD8+ T cells are essential component. However, most immune-based antitumour therapies have had limited efficacy in controlling tumour growth due to immunosuppression within the tumour microenvironment. Experiments described in this thesis were aimed at understanding mechanisms of tumour- mediated immunosuppression of antitumour CTL responses. Studies utilised a BALB/c mouse model comprising renal carcinoma cells (Renca), expressing the haemagglutinin (HA) protein from influenza virus AlPRl8/H1 NI(PR8) as tumour- specific neo-antigen, and transgenic CL4 CD8+ T cells, expressing a high affinity TcR specific for the dominant Kd-restricted epitope of HA. The data show that CL4 CD8+ T cells undergo productive activation (PA) in the tumour draining lymph nodes resulting in CTL responses. However, following migration into the tumour they lose effector function, which is accompanied by an increase in cell- surface expression of Ly6C. However, if the interaction of Ly6C with its unknown ligand is blocked under conditions that would otherwise result in abortive activation then PA is restored. Other studies revealed that endogenous tumour-infiltrating Iymphocytes (TIL) could suppress CL4 CTL activity by elaborating adenosine via CD39 and CD73 ecto-enzymes. However, suppression was prevented by antagonising the adenosine receptors. Further investigations revealed that expression of CD39 and CD73 by endogenous TIL is controlled by TGF-~. Several distinct populations of tumour-infiltrating myeloid-derived suppressor cells (Ti-MDSC) were also characterised based on cell-surface expression of different levels of Ly6C and Ly6G glycoproteins. Not only do their phenotypic profile and relative proportion change over time as the tumours progress, but these Ti-MDSC also express CD39 and CD73. These findings demonstrate that various mechanisms of immunosuppression operate within the tumour microenvironment. Therefore, although targeting individual mechanisms may potentially alleviate some of the suppression; enabling partial restoration of CTL activity, it is likely that only by targeting multiple mechanisms will we be able to fully restore CTL activity to such an extent that the tumour is eradicated. Abstract word count: 325
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available