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.
Authors
- Hugo J.W.L. Aerts (ORCID: https://orcid.org/0000-0002-2122-2003)
- Karin Birkenkamp‐Demtröder (ORCID: https://orcid.org/0000-0001-8057-6277)
- Asbjørn Kjær (ORCID: https://orcid.org/0009-0006-3307-0031)
- Randi Istrup Juul (ORCID: https://orcid.org/0000-0001-7829-9071)
- Iver Nordentoft (ORCID: https://orcid.org/0000-0003-4856-4086)
- Christopher Abbosh (ORCID: https://orcid.org/0000-0002-8983-1382)
- Trine Strandgaard (ORCID: https://orcid.org/0000-0001-8277-8155)
- Lars Dyrskjøt (ORCID: https://orcid.org/0000-0001-7061-9851)
- Mads Agerbæk (ORCID: https://orcid.org/0000-0003-3923-6136)
- Johanne Ahrenfeldt (ORCID: https://orcid.org/0000-0001-9175-0373)
- Nicolai J. Birkbak (ORCID: https://orcid.org/0000-0003-1613-9587)
- Darren Hodgson (ORCID: https://orcid.org/0000-0002-6631-9626)
- Jørgen Bjerggaard Jensen (ORCID: https://orcid.org/0000-0002-4347-739X)
- Nanna Kristjánsdóttir (ORCID: https://orcid.org/0000-0002-4128-7816)
- Deema Radif
Institutions
- Aarhus University Hospital (DK)
- Maastricht University (NL)
- AstraZeneca (Singapore) (SG)
- Artificial Intelligence in Medicine (Canada) (CA)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102101
- Citations
- 4
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 4.18
Funders
- AstraZeneca
- Aarhus Universitet
- Kræftens Bekæmpelse
- Aarhus Universitets Forskningsfond
- Lundbeckfonden
- Novo Nordisk Fonden