Unravelling the role of CD8+ T-cells in immune checkpoint inhibitor induced colitis

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The immune system plays a central role in defence against disease, including cancer. This is achieved by coordination of numerous immune cells, including a subset called T-cells (the 'generals' of the immune system), which identify and co-ordinate the destruction of faulty cells. To differentiate between normal cells in the body and "foreign" cells, the immune system uses "checkpoints" - molecules on T-cells that act as a brake on the immune system and require activation to initiate an immune response. Cancer cells exploit these checkpoints to avoid being attacked by the immune system. Immune check point inhibitors (ICPIs) are drugs that target these checkpoints, to release the 'brakes' and 're-awaken' the immune system and have revolutionized cancer therapy. Examples of such drugs includes ipilimumab and nivolumab, which have been proven to increase survival in patients with advanced cancer including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, and Hodgkin's lymphoma. There is increasing evidence that combination therapy with ipilimumab and nivolumab induces a more effective anti-tumour response, than single therapy alone. It is anticipated that over the next few years, these agents will be approved for treatment of other types of cancer. However, an important consideration is the association of ICPIs with specific toxicities, of which gastrointestinal (GI) toxicity in the form of diarrhoea and colitis (inflammation of the gut) is the most serious. Occurring in up to 50% of patients receiving the more efficacious combination treatment, ICPI-induced colitis can incur significant illness, sometimes leading to hospital admission and even death if not promptly treated. It is also the most common cause of ICPI discontinuation. Successful and timely management is limited by a lack of understanding of the cellular and molecular processes underlying the disease, and whilst there appears to be some similarities with other forms of well-studied colitis such as inflammatory bowel disease (IBD), overall it is probably a distinct entity. Although many patients are treated with high dose steroids and/or additional immunosuppression therapy, these are fraught with yet further sides effects such as serious infections.The aim of the current research is to determine the immunological pathways mediating ICPI-related colitis and identify biological targets for therapy with a view of reducing the severity of this disease and avoiding discontinuation of life prolonging cancer treatment. There is emerging evidence that a subset of T-cells, known as CD8+ cells, are key drivers of inflammation, however the pathways mediating their activation are largely unknown. To provide further insights, I am collaborating with the internationally renowned cancer centres at Guy's Hospital and the Royal Marsden Hospital to access patients treated with combination therapy, and who then develop diarrhoea or colitis. I will analyse blood samples and colonic tissue (taken when patients have a routine colonoscopy for assessment of their disease) using cutting edge laboratory techniques, and compare this to healthy patients and those with IBD. Additionally, I will study interactions between cells of the gut wall (which form the barrier between the body and external environment) and CD8+ cells in great depth using a colonic organoid model system. These are 3D miniaturized and simplified versions of an organ produced in vitro, that show realistic micro-anatomy and provide very rich information about the immune cell/gut wall environment. Importantly, to mitigate against the possibility that CD8+ cells are not the key cells implicated in ICPI- induced colitis, I will also be capturing data on alternative immune cells snd pathways.