Targeting Mediator kinases to improve the efficacy of immunotherapies in colorectal cancer

Despite the promising results of immunotherapies to treat various cancer (eg melanoma), they have been unsuccessful for the vast majority of colorectal cancer patients. The two major limitations are first, immune evasion, the shaping of an immunosuppressive tumour microenvironment (TME) by tumour cells to avoid detection by cytotoxic T-cells and second, a concept called T-cell exhaustion, where chronic stimulation of effector T-cells reduce the effectiveness of T-cell mediated immunity. This presents a major problem of immunotherapies to treat bowel cancer and most other solid tumours. We have recently discovered that two epigenetic regulators CDK8 and CDK19, also known as Mediator kinases, have so far unappreciated roles to control T-cell differentiation and T-cell function by regulating the secretion of effector cytokines. Deletion or inhibition of Mediator kinases reduced the degree of terminal T-cell differentiation, which resulted in an “improved” effector phenotype known to be more effective attacking and destroying tumour cells. Based on these promising findings, we hypothesize that Mediator kinases can be targeted to improve T-cell responses against colon cancer cells and other solid tumour cells. Using colorectal cancer as a model, we will use sophisticated genetic mouse models and organoid models combined with state-of-the-art sequencing approaches to investigate whether targeting Mediator kinases in immune cells can reshape the TME and to increase the efficacy of existing immunotherapies for more beneficial patient outcomes.