Evaluation of cancer-associated fibroblasts (CAFs) to combat therapy resistance in bladder cancer.

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Approximately 50% of locally-advanced and metastatic bladder tumours show enrichment of cancer-associated fibroblasts (CAFs) with increased Transforming Growth Factor-beta signalling and extracellular matrix (ECM) remodelling. Survival outcomes and therapy responses are particularly poor in these "immune-excluded" tumours. The role of CAFs in radiotherapy resistance is poorly understood and likely to be clinically important. In this proposal, immunogenomic and immune phenotyping approaches will characterise CAF-enrichment, the ECM and the wider immune microenvironment in large retrospective tissue collections and a prospective randomised trial using immune checkpoint blockade with standard chemo-radiation. Novel non-invasive biomarkers including urinary TCR-Seq will also be evaluated.