Low T cell diversity is associated with poor outcome in bladder cancer: a comprehensive longitudinal analysis of the T cell receptor repertoire

Abstract

T cells are one of the primary effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. Here we investigated the T cell receptor (TCR) repertoire in patients with bladder cancer. In patients with localized muscle-invasive bladder cancer, low peripheral TCR diversity pre-treatment was associated with poor outcomes, especially when combined with low T cell fraction in circulation. These low-diversity repertoires were dominated by expanded clones that persisted throughout treatment and disproportionately targeted latent viral infections. Longitudinal analysis revealed a reduction in TCR diversity after treatment indicating an adverse effect on the immune system. Single-cell sequencing identified most expanded clones as cytotoxic T cells, while non-expanded clones were predominantly naive T cells. Thus, low TCR diversity after treatment likely represents a contraction of the naive T cell compartment. Our results show that a decrease in immune competency limits the ability to prevent cancer growth and metastatic dissemination, thus underlining the importance of immune health in cancer.