Translational development of novel immunotherapeutic targets in Oesophageal Cancer

食管腺癌（OAC）是一种起源于食物管道内的癌症，与吸烟、肥胖和巴雷特食管（Barrett's Escherapy）等风险因素有关，巴雷特食管是由胃酸从胃流入食管引起的。受这种疾病影响的患者的生存率非常低，因为许多人被诊断为晚期，只有不到一半的人能够接受可能治愈他们的治疗。不幸的是，英国本身是世界上腺癌发病率最高的国家，但这种疾病的治疗选择发展缓慢。一种新型的治疗方法被称为免疫疗法，它在其他类型的癌症（如黑色素瘤的皮肤癌亚型）中显示出了希望。这种治疗方法与目前提供的化疗和放疗不同，后者有许多不必要的副作用。免疫疗法的作用是增强人体自身的免疫系统对抗癌细胞并杀死它们。最近的研究表明，免疫疗法可以改善少数OAC患者的生存率，这在改变这种疾病患者的治疗前景方面表现出巨大的希望。然而，作为一种新型的治疗方法，需要进行更多的工作，以进一步优化它。本提案中详细介绍的计划是我们提高对OAC抗肿瘤反应的认识和理解的机会。我们有一个及时的机会来研究一个目前非常热门的研究领域，因为它有可能改善这种疾病患者的治疗选择。我们知道癌症患者的免疫反应发生了改变，肿瘤细胞能够引起我们免疫细胞的变化，使它们变得不那么有效，我将加入一个对OAC进行基因测序的团队，并在过去3年中确定了OAC免疫反应的一系列新特征。特别是，他们已经确定了白色细胞（T细胞）的亚群，这些细胞可能具有杀死癌细胞的潜力，但在肿瘤中受到抑制。我们现在需要知道为什么会发生这种情况，哪些细胞在杀死肿瘤方面最重要，以及我们如何利用现有的知识开发新的治疗方法。我们将招募在伯明翰伊丽莎白女王医院（QEH）接受食管癌手术的患者。我们将为我们的研究收集组织和血液样本，QEH是英国最大的上消化道癌症手术中心之一。获取患者样本的系统已经牢固建立，并将在整个项目中继续使用。用于实现以下目标的技术已经在研究小组中使用，我们拥有强大的个人网络，可以在必要时用他们的专业知识支持这个项目。在这个提案中，我将：- 研究来自患有OAC的患者的活检样品的不同T细胞亚群的概况和活性，以鉴定最有效的亚型，在肿瘤切片上使用专门的分析来观察哪些T细胞亚群与肿瘤细胞相互作用-在添加免疫调节试剂的情况下用自体实验室生长的小肿瘤培养T细胞，以评估它们增加T细胞识别和对肿瘤的细胞毒性的能力。我希望开发新的临床靶点，将其转化为OAC患者的治疗方法，以提高这种疾病的生存机会。

Oesophageal adenocarcinoma (OAC) is a type of cancer that originates within the food pipe and is associated with risk factors such as smoking, obesity and a condition caused Barrett's Oesophagus which is caused by a build-up of acid flowing from the stomach into the oesophagus. Patients affected by this disease have a very poor survival rate as many are diagnosed late, with less than half able to have treatment that could potentially cure them. Unfortunately, the UK itself has the highest incidence of adenocarcinoma in the world, yet treatments options for this disease have been slow to develop. A new type of treatment that has shown promise in other types of cancer, such as the skin cancer subtype of melanoma, is known as immunotherapy. This treatment is different to those currently offered such as chemotherapy and radiotherapy which have many unwanted side effects. Immunotherapy acts to boost the body's own immune system against the cancer cells and kill them. Recent research has shown that immunotherapy can improve survival for a minority of patients with OAC demonstrating great promise in transforming the treatment landscape of patients with this disease. However, as a new type of treatment, more work needs to be carried in order to optimise it further. The plan detailed in this proposal is our chance to improve our knowledge and understanding of the anti-tumour response in OAC. We have a timely opportunity to study an area of research that is currently highly topical due to the potential to improve treatment options in patients with this disease. We know that the immune response in patients with cancer is altered and that tumour cells are able to cause changes to our immune cells making them less effective, I will join a team that has genetically sequenced OAC and has also identified a range of novel features in the immune response to OAC over the last 3 years. In particular, they have identified subsets of white cells (T cells) that may have the potential to kill cancer cells but are suppressed within the tumour. We now need to know why this occurs, which cells are most important in killing tumour and how we can use our current knowledge to develop new treatment approaches. We will be recruiting patients undergoing operations to remove their oesophageal cancer at Queen Elizabeth Hospital (QEH), Birmingham. We will be collecting tissue and blood samples for our research and the QEH is one of the largest centres in the UK for upper GI cancer operations. The system for obtaining patient samples is already strongly established and will continue throughout this project. The techniques used to fulfil the objectives outlined below are already in use within the research group, and we possess a strong network of individuals that can support this project with their expertise when necessary.In this proposal I will: -study the profile and activity of different T cell subsets from biopsy samples of patients with OAC in order to identify the most potent subtypes -use specialised analysis on tumour sections to see which T cell subsets are interacting with tumour cells -culture T cells with autologous lab-grown mini-tumours with the addition of immune modulating reagents in order to assess their ability to increase T cell recognition and cytotoxicity towards the tumour.Building on this work, I hope to develop new clinical targets which will translate into treatments for patients with OAC to improve the chances of survival in this disease.