Identification of novel epigenetic targets to re-activate exhausted and senescent T-cells

A newly established collaboration between the UK SPINE Hubs Oxford University, Birmingham University and the Drug Discovery Institute in Dundee (DDU) is aiming to identify key epigenetic regulators of T-cell exhaustion and T-cell senescence through the use of epigenetic tool compounds. The project is funded through a PoC Bridge Programme award by the UK SPINE.

As humans live longer, a key concern is to find ways to maintain health as they age. Immunity declines during ageing, with hallmarks such as increased susceptibility to infections, reduced vaccination response, persistent viral infections, increased autoimmunity and a rise in inflammatory syndromes. However, mechanisms that drive age-related immune dysfunction are poorly understood, and therefore specific strategies to restore immune responsiveness in older people are limited. Evidence points to epigenetic regulation of T-cell phenotypes playing a critical role, and we aim to interrogate this further by assessing T-cell activity in patient samples of individuals aged over 65, and T-cells from a cohort with persistent viral infections.

We initiated a collaborative project between 3 UK SPINE hubs at Oxford, Birmingham and Dundee to identify key epigenetic regulators of T-cell exhaustion and senescence. We will perform an unbiased phenotypic screen of a panel of 60 potent and selective small molecule epigenetic inhibitors developed by the Structural Genomic Consortium (SGC) in phenotypic assays for T-cell exhaustion and senescence. Screening assays will be designed collaboratively between the Dundee DDU, Oxford (SGC and TGU) and University of Birmingham and performed on pooled human peripheral blood mononuclear cells (PBMC) at Oxford and Birmingham University. Prof. Eleanor Barnes (University of Oxford) will be leading the project on T-cell exhaustion, utilizing her extensive clinical samples from patients infected with chronic viruses like HBV, HCV and HIV. Prof. Janet Lord’s group (University of Birmingham) will be performing a compound screen on senescent cells from her patient cohort of individuals aged over 65. Upon results from the initial phenotypic screen, hit compounds will be used to elucidate epigenetic mechanisms of T-cell exhaustion and senescence, and the top screening hits will be further assessed in collaboration with the DDU Dundee.

Downstream, epigenetic compound tools will have the capacity to re-activate the T-cell response and will be used for follow-on pre-clinical translational projects: initially, lead compounds can be further developed and optimized in collaboration with the DDU Dundee. Options for further pre-clinical and clinical development include partnerships programmes with pharmaceutical companies as previously exploited by DDU Dundee, or a spin out company. In addition to benefitting downstream translational drug development, epigenetic compounds can also act as tools to gain a deeper understanding of the biological mechanisms driving T-cell exhaustion and senescence.