TY - JOUR
T1 - Low T cell diversity associates with poor outcome in bladder cancer
T2 - A comprehensive longitudinal analysis of the T cell receptor repertoire
AU - Kjær, Asbjørn
AU - Kristjánsdóttir, Nanna
AU - Juul, Randi Istrup
AU - Nordentoft, Iver
AU - Birkenkamp-Demtröder, Karin
AU - Ahrenfeldt, Johanne
AU - Strandgaard, Trine
AU - Radif, Deema
AU - Hodgson, Darren
AU - Abbosh, Christopher
AU - Aerts, Hugo J.W.L.
AU - Agerbæk, Mads
AU - Jensen, Jørgen Bjerggaard
AU - Birkbak, Nicolai J.
AU - Dyrskjøt, Lars
N1 - Funding Information:
All of the computing for this project was performed on the GenomeDK cluster. We thank GenomeDK and Aarhus University for providing computational resources and support that contributed to these research results. The authors acknowledge funding received in support of the project from AstraZeneca , the Danish Cancer Society , the Novo Nordisk Foundation , the Lundbeck Foundation , and the Aarhus University Research Foundation .
Publisher Copyright:
© 2025 The Author(s)
PY - 2025/5/20
Y1 - 2025/5/20
N2 - 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.
AB - 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.
KW - biomarkers
KW - bladder cancer
KW - cancer genomics
KW - cancer immunology
KW - muscle-invasive bladder cancer
KW - next-generation sequencing
KW - single-cell sequencing
KW - T cell receptors
KW - TCR sequencing
U2 - 10.1016/j.xcrm.2025.102101
DO - 10.1016/j.xcrm.2025.102101
M3 - Article
SN - 2666-3791
VL - 6
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 5
M1 - 102101
ER -