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

L. Llaó-Cid, Wong Jkl, I. Fernandez Botana, Y. Paul, M. Wierz, Pilger L-M, A. Floerchinger, Tan Cl, S. Gonder, G. Pagano, M. Chazotte, K. Bestak, C. Schifflers, M. Iskar, T. Roider, F. Czernilofsky, Bruch P-M, Mallm Jp, A. Cosma, Campton de, E. Gerhard-Hartmann, A. Rosenwald, D. Colomer, E. Campo, D. Schapiro, Green Ew, S. Dietrich, P. Lichter, E. Moussay, J. Paggetti, M. Zapatka and M. Seiffert ()
Additional contact information
L. Llaó-Cid: German Cancer Research Center (DKFZ)
Wong Jkl: German Cancer Research Center (DKFZ)
I. Fernandez Botana: Luxembourg Institute of Health
Y. Paul: German Cancer Research Center (DKFZ)
M. Wierz: Luxembourg Institute of Health
Pilger L-M: German Cancer Research Center (DKFZ)
A. Floerchinger: German Cancer Research Center (DKFZ)
Tan Cl: German Cancer Research Center
S. Gonder: Luxembourg Institute of Health
G. Pagano: Luxembourg Institute of Health
M. Chazotte: Heidelberg University and Heidelberg University Hospital
K. Bestak: Heidelberg University and Heidelberg University Hospital
C. Schifflers: German Cancer Research Center (DKFZ)
M. Iskar: German Cancer Research Center (DKFZ)
T. Roider: University Hospital Heidelberg
F. Czernilofsky: University Hospital Heidelberg
Bruch P-M: University Hospital Heidelberg
Mallm Jp: German Cancer Research Center
A. Cosma: Luxembourg Institute of Health
Campton de: RareCyte
E. Gerhard-Hartmann: University of Würzburg
A. Rosenwald: University of Würzburg
D. Colomer: CIBERONC
E. Campo: CIBERONC
D. Schapiro: Heidelberg University and Heidelberg University Hospital
Green Ew: German Cancer Research Center
S. Dietrich: University Hospital Heidelberg
P. Lichter: German Cancer Research Center (DKFZ)
E. Moussay: Luxembourg Institute of Health
J. Paggetti: Luxembourg Institute of Health
M. Zapatka: German Cancer Research Center (DKFZ)
M. Seiffert: German Cancer Research Center (DKFZ)

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61822-x

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