Bottomley Group | Immunity of Ageing

Exploring the translational impact of immune ageing and pharmacological immunosuppression upon peripheral immunity to viruses and malignancy

Immunofluorescence image showing: (left) CD8 infiltration at the leading edge of cutaneous squamous cell carcinoma. Blue = nuclei; Green = pan-cytokeratin; Red = CD8; White polygons = regions chosen for high-resolution spatial transcriptomic analysis. (right) serial section of same tumour. Cyan = nuclei; Green = pan-cytokeratin; purple = CD45; white boxes = regions chosen for single-cell spatial profiling

A transplant is the most effective treatment for advanced kidney disease. As a result, we are transplanting more and more people each year. Because kidney disease is most common in older people, the average age of transplant recipients is increasing. Advances in recent years have significantly improved the short-term outcome of patients who receive a transplant, but long-term outcomes remain modest. This is partly due to the medication that must be given to prevent the immune system attacking the transplant (‘immunosuppression’). Over time, this medication damages the transplant and makes patients more prone to infection and cancer.

Our research focuses using markers in the immune system to identify patients who may be at risk of complications after a renal transplant. We particular focus on exploring the effect of ageing in the immune system on transplant outcomes. As we age the immune system undergoes several changes through long-term exposure to viruses and other factors in the environment. We refer to these changes as ‘immunosenescence’ (immune ageing). Over time, this can lead to the immune system being less effective at protecting us from infection and less responsive to vaccination.

Our current work focuses on changes that occur within the immune cells present in the skin prior to the development of skin cancer; specifically we are interested in the impact of immune ageing combined with the use of immunosuppression after transplantation. To evaluate this we use a combination of functional immunological assays and high-resolution spatial transcriptomic analysis.

Our work may ultimately allow clinicians to use the immune system in clinical practice in the future, to guide the type and amount of immunosuppression we give to transplant recipients. Being able to identify patients who may safely take less immunosuppression may reduce the problems encountered by patients partly as a result of these drugs, including cancer and infection. Our work may identify new pathways that can be manipulated to encourage the immune system to fight off cancerous cells. Drugs that suppress the immune system are used in many other conditions, such as in autoimmune conditions, and our findings have relevance to these populations too.

Our research has been generously funded by the Wellcome Trust, British Skin Foundation, Oxford Hospitals Charity, Cancer Research UK and the Chinese Academy of Medical Sciences.