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Title: T-cell cancer immunotherapy : characterisation and manipulation of tumour antigen-specific T cell subsets for adoptive immunotherapy in mouse models
Author: White, Matthew
ISNI:       0000 0004 2713 5044
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Understanding the behaviour of T cells in context of tumour responses is crucial for designing adoptive immunotherapy strategies. The aim of the study is to characterise tumour-specific T cells, including conventional and regulatory T cells (Tregs), in tumour-bearing mice after adoptive transfer. Male-specific minor histocompatibility antigen HY was used as the tumour-associated antigen, expressed by MB49 murine bladder carcinoma and recognised by TCR transgenic CD4 (Marilyn) and CD8 (Matahari) T cells. Unlike male skin grafts, MB49 tumours express a panel of immune-suppressive molecules including PD-L1, FAS-L, TGF-β, IL-10 and IDO which contribute to the formation of a tolerogenic microenvironment. As a result, HY-specific CD8 T cells reject syngeneic male skin grafts but not MB49 tumours. In response to MB49 tumours, HY-specific Tregs underwent expansion. A fraction of proliferating Tregs also lost FoxP3 and became ex-Tregs, which upregulated IFNγ, and downregulated a panel of Treg-specific genes. In addition, it was observed that preferential ex-Treg differentiation took place in an IL-6-enriched microenvironment, such as in the mesenteric lymph nodes. The antigen-specific CD8 response to MB49 is insufficient for rejection. Retroviral modification of MB49 to express hIL-2 allows for induction of effective antigen-specific CD8 responses, providing a potent whole cell in vivo vaccine strategy for exploring factors mediating immune evasion. Finally, the role of anti-HY TCR transgenic T cells in GvHD is assessed. Lymphopenic male recipients lose weight after adoptive transfer of CD4 but not CD8 T cells. With radiation preconditioning, full-blown GvHD ensues, raising questions about this combination for clinical therapy. This study advances knowledge of antigen-specific T effector and Treg responses to HY in a range of environments, including MB49 tumours, male skin grafts and GvHD. It highlights the importance of understanding not only induction of effector responses, but potentially harmful side-effects of adoptive cell transfer.
Supervisor: Chai, Jian Guo ; Dyson, Julian Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral