Advances in Immunotherapy may hold the key to address thr key unmet clinical need presented by incurable metastatic cancers. Immunotherapies, including NK cell therapies, also have the advantage of potentially being effective across a range of cancer types. The purpose of this work is twofold: firstly, HDACi are drugs have been proposed as a repurposed drugs for cancer and there are many clinical trials proposed and ongoing, particularly as they are already approved for clinical use. These drugs remove acetylation groups from histones, interfere with chromatin organisation and generally inhibit gene transcription within cells. However, HDACi cover a spectrum of drugs and little is known about the interactions of specific drugs with the immune system; this gap in knowledge is particularly critical for patients where immunotherapy is already standard of care. There are only a few studies on HDACi and NK cells, and the results are conflicting in terms of enhancing or inhibiting their immune functions. This project will focus on investigating the ability of different HDACi to impact on NK cell metabolic and functional exhaustion in patients with metastatic cancer. Given the known link the between HDACi and histone acetylation, we will initially focus our efforts on reversing and understanding the histone acetylation defect we have found in NK cells from metastatic breast cancer patients. We will also investigate if our findings on NK cell metabolic exhaustion in patients with metastatic breast cancer apply to other cancer types. We are focussing on metastatic melanoma as it is a common cancer with NK cell functional defects, and which shows promise in terms of immunotherapeutic interventions. Overall, this work will identify HDACi that are likely to be beneficial in NK cell immunotherapies and that can be rapidly translated across a range of metastatic cancer types.
