Low T cell diversity associates with poor outcome in bladder cancer: A comprehensive longitudinal analysis of the T cell receptor repertoire.

T cells are crucial effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. Here, we investigate the clinical relevance of the T cell receptor (TCR) repertoire in patients with bladder cancer. In advanced-stage disease, low pre-treatment peripheral TCR diversity is associated with worse overall survival (p = 0.024), particularly when coupled with low circulating T cell fractions (p = 0.00049). These low-diversity repertoires are dominated by hyper-expanded clones that persist throughout treatment. Further longitudinal analysis reveals reductions in TCR diversity after treatment, indicating adverse effects on the immune system. In early-stage disease, immunotherapy increases TCR diversity in patients with good outcomes. Furthermore, single-cell sequencing identifies most hyper-expanded clones as cytotoxic T cells, while non-expanded clones are predominantly naive T cells. Overall, this highlights TCR diversity as a promising biomarker, offering opportunities for tailored oncological treatments to enhance clinical outcomes.