Characterising Cancer Specific Cytotoxic T-cells in patients with Malignant Pleural Effusion (MPE)

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Individuals with cancer are characterised by dysfunctional anti-tumor T-cell responses. The importance of tumour-specific T-cell responses for controlling cancer initiation and development is highlighted by recent clinical trial success of antagonistic monoclonal antibodies, targeting inhibitory immune receptors (EG: PD-1 and CTLA4). However only a proportion of patients respond to currently available immune-checkpoint blockade therapy. Hence an in depth understanding of cancer specific T-cell responses in patients is required, specifically on what antigen is targeted, alongside when and how the patients immune system has lost control of fighting the malignancy. Malignant pleural effusion (MPE) describes the accumulation of fluid and cancer cells in the pleura; the space between the chest wall and the lungs. MPE is often detected in metastatic cancer patients diagnosed with primary lung or breast cancer. Additionally, MPE is also present in mesothelioma patients; the primary cancer of the pleural space. The presence of MPE is of prognostic significance and may indicate the presence of an advanced cancer that is likely unresectable. This D.Phil. project will focus on characterising cancer-specific T-cells isolated from malignant pleural effusion. This is facilitated by taking advantage of the large patient cohort in The Oxford Pleural Effusion trial led by Professor Rahman. Additionally, this project is enabled through ratified methodologies for isolating and expanding cancer-specific T-cells and autologous cancer cell lines established in the Dong group and close collaborators. The focus will be to identify common cancer antigens targeted by tumour-specific cytotoxic T-cells, and determine the key molecular signals that switch anti-tumour immune responses from "functional" to "dysfunctional". These may include antigen sensitivity, immune killing capacity, metabolic potentials, proliferation and potential for functional recovery. Special attention will be paid on identifying T-cell subsets with the potential to control the cancer metastasis through utilisation and development of adoptive T-cell therapy.