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

Asbjørn Kjær; Nanna Kristjánsdóttir; Randi Istrup Juul; Iver Nordentoft; Karin Birkenkamp-Demtröder; Johanne Ahrenfeldt; Trine Strandgaard; Deema Radif; Darren Hodgson; Christopher Abbosh; Hugo J.W.L. Aerts; Mads Agerbæk; Jørgen Bjerggaard Jensen; Nicolai J. Birkbak; Lars Dyrskjøt

doi:10.1016/j.xcrm.2025.102101

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

Asbjørn Kjær, Nanna Kristjánsdóttir, Randi Istrup Juul, Iver Nordentoft, Karin Birkenkamp-Demtröder, Johanne Ahrenfeldt, Trine Strandgaard, Deema Radif, Darren Hodgson, Christopher Abbosh, Hugo J.W.L. Aerts, Mads Agerbæk, Jørgen Bjerggaard Jensen, Nicolai J. Birkbak^*, Lars Dyrskjøt^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Abstract

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.

Originalsprog	Engelsk
Artikelnummer	102101
Tidsskrift	Cell Reports Medicine
Vol/bind	6
Nummer	5
ISSN	2666-3791
DOI	https://doi.org/10.1016/j.xcrm.2025.102101
Status	Udgivet - 20 maj 2025

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10.1016/j.xcrm.2025.102101Licens: CC BY

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Kjær, A., Kristjánsdóttir, N., Juul, R. I., Nordentoft, I., Birkenkamp-Demtröder, K., Ahrenfeldt, J., Strandgaard, T., Radif, D., Hodgson, D., Abbosh, C., Aerts, H. J. W. L., Agerbæk, M., Jensen, J. B., Birkbak, N. J., & Dyrskjøt, L. (2025). Low T cell diversity associates with poor outcome in bladder cancer: A comprehensive longitudinal analysis of the T cell receptor repertoire. Cell Reports Medicine, 6(5), Artikel 102101. https://doi.org/10.1016/j.xcrm.2025.102101

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

abstract = "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.",

keywords = "biomarkers, bladder cancer, cancer genomics, cancer immunology, muscle-invasive bladder cancer, next-generation sequencing, single-cell sequencing, T cell receptors, TCR sequencing",

author = "Asbj{\o}rn Kj{\ae}r and Nanna Kristj{\'a}nsd{\'o}ttir and Juul, {Randi Istrup} and Iver Nordentoft and Karin Birkenkamp-Demtr{\"o}der and Johanne Ahrenfeldt and Trine Strandgaard and Deema Radif and Darren Hodgson and Christopher Abbosh and Aerts, {Hugo J.W.L.} and Mads Agerb{\ae}k and Jensen, {J{\o}rgen Bjerggaard} and Birkbak, {Nicolai J.} and Lars Dyrskj{\o}t",

year = "2025",

month = may,

day = "20",

doi = "10.1016/j.xcrm.2025.102101",

language = "English",

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Kjær, A , Kristjánsdóttir, N , Juul, RI , Nordentoft, I, Birkenkamp-Demtröder, K, Ahrenfeldt, J , Strandgaard, T , Radif, D, Hodgson, D, Abbosh, C, Aerts, HJWL, Agerbæk, M, Jensen, JB , Birkbak, NJ & Dyrskjøt, L 2025, 'Low T cell diversity associates with poor outcome in bladder cancer: A comprehensive longitudinal analysis of the T cell receptor repertoire', Cell Reports Medicine, bind 6, nr. 5, 102101. https://doi.org/10.1016/j.xcrm.2025.102101

Low T cell diversity associates with poor outcome in bladder cancer: A comprehensive longitudinal analysis of the T cell receptor repertoire. / Kjær, Asbjørn ; Kristjánsdóttir, Nanna ; Juul, Randi Istrup et al.
I: Cell Reports Medicine, Bind 6, Nr. 5, 102101, 20.05.2025.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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

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

UR - http://www.scopus.com/inward/record.url?scp=105004382535&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2025.102101

DO - 10.1016/j.xcrm.2025.102101

M3 - Journal article

C2 - 40315845

AN - SCOPUS:105004382535

SN - 2666-3791

VL - 6

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 5

M1 - 102101

ER -

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

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