Chen, Y; (2017) Functional characterisation of tumour-specific T cell responses in pancreatic cancer. Doctoral thesis , UCL (University College London).

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Abstract

BACKGROUND AND AIMS: Pancreatic cancer (PC) has a poor prognosis and effective diagnostic tools and therapies are currently unavailable. This project has explored the role of T cell responses in PC patients as a potential therapy. METHODS: Serum mesothelin (MSLN) levels were tested in patients with pancreatic diseases. CD4+ and CD8+ T cell responses against full-length overlapping MSLN peptide pools were identified. CEA691, together with pre-chosen MSLN547 and WT1-126 were used to stimulate T cell lines from PC patients. Antigen-specific function and phenotype were characterised in the ex-vivo expanded T cell lines after repeated Ag exposure. Further experiments used inhibitory receptor blockade to augment the function of T cells isolated from cancer patients. RESULTS: Soluble MSLN was elevated in PC patients compared to normal controls, but could not distinguish the malignant from benign pancreatic disease. MSLN-specific CD4+ T cell responses were significantly increased in PC patients compared to controls, indicating an expansion of MSLN-specific CD4+ T cell in PC patients, and new epitopes were identified. It was possible to generate CEA691, WT126 and MSLN547-specific HLA-A*02 restricted T cell lines from PC patients. The ex vivo expanded CEA691-specific T cells demonstrated Ag-specific cytotoxicity and were able to recognize and kill HLA-A2+ CEA+ pancreatic cell lines in vitro. Blockade of PD-1 and TIM-3 further enhanced T cell function in vitro. CONCLUSION: We found that tumour associated antigen (TAA)-specific T cells were identifiable in the peripheral repertoire of patients with pancreatic cancer, and the function of these cells were preserved in some cases. Such antigen-specific function and cytotoxicity was more common in relatively early stages of the disease than the terminal stage, and PD-L1 blockade further improved the responses, suggesting that TAA-specific T cells together with checkpoint inhibition could be potential strategies for the treatment of pancreatic cancer.

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