Advancing immunotherapy by analysing inhibitory receptor expression and function ex vivo

Adoptive cell therapy (ACT) and immune checkpoint blockade (ICB) are transformative cancer immunotherapy methods. ACT involves extracting, expanding, genetically modifying, and reintroducing T cells to target specific cancers. While highly effective in treatment of haematological malignancies, its effectiveness in solid tumours is poor mainly due to the immunosuppressive tumour environment and the quality of the transferred cells. A strategy to improve ACT involves inhibiting checkpoint functions of inhibitory receptors, cell surface receptors that inhibit T cell function, in transferred cells to achieve high efficacy T cells. Despite the potential of about 60 immune checkpoints to be manipulated for creating optimal T cells, fewer than 15% are currently targeted. This is due to limited understanding of their inhibitory mechanisms and the distinct roles different inhibitory receptors play at various T-cell differentiation stages. This proposal aims to systematically characterise the biology of inhibitory receptors on T cells to leverage this information for improving ACT. This involves understanding immune checkpoint expression and signalling during ex vivo expansions and how these receptors affect the behaviour of expanded T cells. The insight from this will guide engineering of T cells with designer phenotypes crucial for effective ACT.