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

恶性胸腔积液 (MPE) 患者癌症特异性细胞毒性 T 细胞的特征分析

• 批准号: 2436376
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2436376
• 关键词: Characterising; Cancer; Specific; Cytotoxic; cells

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.

患有癌症的个体的特征在于功能失调的抗肿瘤T细胞应答。肿瘤特异性T细胞应答对于控制癌症起始和发展的重要性通过靶向抑制性免疫受体（EG：PD-1和CTLA 4）的拮抗性单克隆抗体的最近临床试验成功而突出。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。恶性胸腔积液（MPE）描述了胸腔积液和癌细胞在胸膜（胸壁和肺之间的空间）中的积聚。MPE通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，MPE也存在于间皮瘤患者中;胸膜腔的原发性癌症。MPE的存在具有预后意义，并可能表明存在可能无法切除的晚期癌症。 这个D. Phil该项目将重点关注从恶性胸腔积液中分离出的癌症特异性T细胞的特征。这是通过利用Rahman教授领导的牛津胸腔积液试验中的大型患者队列来促进的。此外，该项目通过批准的方法来实现，用于分离和扩增Dong组和密切合作者建立的癌症特异性T细胞和自体癌细胞系。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“功能性”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。将特别关注通过利用和开发过继性T细胞疗法来识别具有控制癌症转移潜力的T细胞亚群。