Characterising genetic determinants of response to immune checkpoint blockade at the single cell level (360G-Wellcome-226535_Z_22_Z)

Background Immune checkpoint blockade (ICB) re-invigorates T cells rendered exhausted by tumours and has revolutionised the treatment of cancers, including melanoma. However, clinical outcomes are heterogenous and ICB frequently triggers serious, multi-organ autoimmune complications. This clinical heterogeneity likely reflects inter-individual variation in sensitivity to ICB activity- the determinants of which are unresolved and contribution of germline genetics unexplored.I have previously shown T cell clonality and baseline expression influence survival. I hypothesise that genetic variation influences ICB responses in a cell-type specific manner, with consequences for patient outcomes. Research Proposed Using scRNA-seq with TCR-seq, I will systematically characterise peripheral immunocytes in terms of counts, gene expression and clonality, across samples from a longitudinal patient cohort (n>280) I initiated. Results will be integrated with tumour mutational burden and clinical outcomes. Leveraging the large effect-sizes of regulatory variants, I will use genetics to explore interactions between gene- expression and ICB response. Using TCR-seq data I will delineate determinants and targets of long-lived T cell clones in patients with durable responses. Envisaged Outcomes A comprehensive cell-atlas with relevance to oncological responses, autoimmunity and immunodeficiency, describing inter-individual variation and the contribution of genetics to ICB responses and the identification of T cell markers of remission.