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Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target

T-cell exhaustion contributes to immunotherapy failure in chronic lymphocytic leukemia (CLL). Here, we analyze T cells from CLL patients’ blood, bone marrow, and lymph nodes, as well as from a CLL mouse model, using single-cell RNA sequencing, mass cytometry, and tissue imaging. T cells in CLL lymph...

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Main Authors: Llaó Cid, Laura (Author) , Wong, J. K. L. (Author) , Fernandez Botana, I. (Author) , Paul, Yashna (Author) , Wierz, M. (Author) , Pilger, Liesa-Marie (Author) , Floerchinger, Alessia (Author) , Tan, Chin Leng (Author) , Gonder, S. (Author) , Pagano, G. (Author) , Chazotte, Margot (Author) , Bestak, Kresimir (Author) , Schifflers, C. (Author) , Iskar, M. (Author) , Roider, Tobias (Author) , Czernilofsky, Felix (Author) , Bruch, Peter-Martin (Author) , Mallm, Jan-Philipp (Author) , Cosma, A. (Author) , Campton, D. E. (Author) , Gerhard-Hartmann, E. (Author) , Rosenwald, A. (Author) , Colomer, D. (Author) , Campo, E. (Author) , Schapiro, Denis (Author) , Green, Edward W. (Author) , Dietrich, Sascha (Author) , Lichter, Peter (Author) , Moussay, E. (Author) , Paggetti, J. (Author) , Zapatka, Marc (Author) , Seiffert, M. (Author)
Format: Article (Journal)
Language:English
Published: 07 August 2025
In: Nature Communications
Year: 2025, Volume: 16, Pages: 1-22
ISSN:2041-1723
DOI:10.1038/s41467-025-61822-x
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-61822-x
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-61822-x
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Author Notes:L. Llaó-Cid, J.K.L. Wong, I. Fernandez Botana, Y. Paul, M. Wierz, L.-M. Pilger, A. Floerchinger, C.L. Tan, S. Gonder, G. Pagano, M. Chazotte, K. Bestak, C. Schifflers, M. Iskar, T. Roider, F. Czernilofsky, P.-M. Bruch, J.P. Mallm, A. Cosma, D.E. Campton, E. Gerhard-Hartmann, A. Rosenwald, D. Colomer, E. Campo, D. Schapiro, E.W. Green, S. Dietrich, P. Lichter, E. Moussay, J. Paggetti, M. Zapatka & M. Seiffert
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Summary:T-cell exhaustion contributes to immunotherapy failure in chronic lymphocytic leukemia (CLL). Here, we analyze T cells from CLL patients’ blood, bone marrow, and lymph nodes, as well as from a CLL mouse model, using single-cell RNA sequencing, mass cytometry, and tissue imaging. T cells in CLL lymph nodes show the most distinct profiles, with accumulation of regulatory T cells and CD8+ T cells in various exhaustion states, including precursor (TPEX) and terminally exhausted (TEX) cells. Integration of T-cell receptor sequencing data and use of the predicTCR classifier suggest an enrichment of CLL-reactive T cells in lymph nodes. Interactome studies reveal potential immunotherapy targets, notably galectin-9, a TIM3 ligand. Inhibiting galectin-9 in mice reduces disease progression and TIM3+ T cells. Galectin-9 expression also correlates with worse survival in CLL and other cancers, suggesting its role in immune evasion and potential as a therapeutic target.
Item Description:Online veröffentlicht: 07. August 2025
Gesehen am 21.01.2026
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-025-61822-x

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