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Title: Functional analysis of tumour specific effector and regulatory T cells in vivo : implications for cancer immunotherapy
Author: Coe, David John
ISNI:       0000 0004 2709 9004
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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MB49, an H2b+ murine bladder carcinoma cell line, naturally expresses the male-specific minor histocompatibility antigen, HY, which can be used as a proxy tumour associated antigen. The MB49 cell line, together with two HY-specific TCR-transgenic mouse strains (as sources of tumour-specific CD4 and CD8 T cells), form a unique system in which anti-tumour T cell responses can be manipulated and analysed. I have studied some basic but critical immunological aspects of MB49 cells, adoptively transferred T cells and an immunotherapeutic antibody. I confirmed that MB49 cells express all three defined HY genes (Dby, Uty and Smcy), and demonstrated that cultured and freshly isolated tumour cells display a distinct phenotype. I found that MB49 tumours are very aggressive even though they are clearly immunogenic. Female B6 mice are more efficient than males at controlling MB49 tumours, especially when inoculated with a low tumour dose, suggesting that HY-specific T cell responses make a significant contribution to immune control of MB49 tumours. I evaluated three different immunotherapies for treating MB49 tumours: Whole body irradiation followed by the adoptive transfer of Tumour Associated Antigen specific CD4 T cells, or IL-15 expressing CD8 T cells, were found to inhibit the growth of MB49 tumours. Administration of anti-GITR mAbs was found to be very effective at eliminating established MB49 tumours. I observed a novel role for IL-2 in immunoregulation; by the suppression of the differentiation of IL-17-producing Th17 cells. Finally, I demonstrated that Transforming Growth Factor β is essential for the tumour-induced expansion of natural regulatory T cells. This study not only extends the current knowledge of the immunobiology of MB49 tumours but also lays a foundation for further investigation with respect to designing rational T cell cancer immunotherapy using genetically manipulated, tumour-specific T cells.
Supervisor: Chai, Jian-Guo ; Dyson, Julian Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral