Understanding the pathophysiology of auto-immunity through Immune Checkpoint Blockade

Cancer immunotherapy consisting of Immune Checkpoint Blockade (ICB) has reshaped management and outcomes for many cancers, but frequently elicits autoimmune side-effects (immune-related adverse events – irAEs) that are a source of significant morbidity, and are sometimes fatal. The determinants of irAEs are poorly understood, especially why divergent organ systems become involved in different patients. I will explore the relationship between patient T Cell receptor (TCR) repertoire, HLA and the mutations within the cancer to better understand precipitants of organ-specific irAEs and similarities with autoimmunity. To do this, I will perform spatial transcriptomics and TCR profiling of skin and knee joint irAEs and compare this with existing spatial datasets from autoimmune disease to investigate the similarities and differences in local immune environments. I will then move on to a longitudinal in-house cohort of patients to perform tumour exome and TCR sequencing, integrating this with TCR/RNA sequencing of peripheral lymphocytes at various timepoints in their ICB treatment, with the aim of understanding the mechanisms behind development of irAEs. Finally, I will interrogate large public cancer and autoimmune TCR-antigen datasets, building deep learning models to study how the interaction between TCR, HLA and putative peptide affects autoimmunity.