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

癌症患者的特征是功能失调的抗肿瘤t细胞反应。最近针对抑制性免疫受体（如PD-1和CTLA4）的拮抗单克隆抗体的临床试验成功强调了肿瘤特异性t细胞反应在控制癌症发生和发展中的重要性。然而，只有一部分患者对目前可用的免疫检查点阻断疗法有反应。因此，需要深入了解患者的癌症特异性t细胞反应，特别是针对什么抗原，以及患者的免疫系统何时以及如何失去对恶性肿瘤的控制。恶性胸膜积液（MPE）是指胸膜内积液和癌细胞；胸壁和肺之间的空间。MPE常在诊断为原发性肺癌或乳腺癌的转移性癌症患者中检测到。此外，间皮瘤患者也存在MPE；胸膜间隙的原发癌。MPE的存在具有预后意义，可能表明存在可能无法切除的晚期癌症。这种哲学博士。项目将重点研究从恶性胸腔积液中分离的癌症特异性t细胞的特征。这得益于Rahman教授领导的牛津胸腔积液试验中大量患者队列的优势。此外，该项目通过经批准的方法来分离和扩增癌症特异性t细胞和由Dong团队及其密切合作者建立的自体癌细胞系。重点将是识别肿瘤特异性细胞毒性t细胞靶向的常见癌症抗原，并确定将抗肿瘤免疫反应从“功能”转换为“功能失调”的关键分子信号。这些可能包括抗原敏感性、免疫杀伤能力、代谢潜力、增殖和功能恢复潜力。将特别关注识别t细胞亚群，通过利用和发展过继t细胞治疗来控制癌症转移的潜力。

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.