Translational development of novel immunotherapeutic targets in Oesophageal Cancer

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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.