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

Active: 2019.11.01 - 2021.09.30
UK SPINE Scientific Liaison: Monica Spisar

T cells are key players of the immune system and kill infected or dysregulated cells such as cancer cells. In the elderly and individuals with chronic viral infection, T cells have reduced ability to adequately respond and protect. This work aims to identify molecules that re-activate T cells using an unbiased screening approach.

It is hypothesized that, in comparison to targeting checkpoint inhibitors alone, complementary modification of epigenetic signatures of exhausted and senescent T cells may lead to increased and more durable effective T cell responses.

In this project, epigenetic inhibitors' potential to reactivate exhausted and senescent T cells toward translation of hits to therapeutic interventions for aging will be investigated.

Via an unbiased phenotypic screen of a panel of 54 potent and selective small molecule epigenetic inhibitors in T cell assays, exhaustion and senescence will be assessed. Screening assays will be performed on pooled human peripheral blood mononuclear cells from individuals aged over 65 and from a cohort with persistent viral infection.

Epigenetic mechanisms of T cell exhaustion and senescence will be elucidated; ChipSeq/ChipPCR will be used to investigate alterations in epigenetic regulation pre- and post-treatment for hit compounds. T cell killing assays will confirm enhanced post-treatment activity of exhausted T cells.

Compound properties of the top screening hits will be further assessed: initial in vitro ADME data for three compounds will initiate translational development.

All outputs will be shared in publicly-accessible repositories.