Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target PMID: 40775219

Target-related Cytokines

2026-09-23

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

Nat Commun. 2025 Aug 7;16(1):7271. doi: 10.1038/s41467-025-61822-x.

L Llaó-Cid ^# ¹ , Jkl Wong ^# ¹ , I Fernandez Botana ² , Y Paul ¹ , M Wierz ² , L-M Pilger ¹ ³ , A Floerchinger ¹ ³ , C L Tan ⁴ , S Gonder ² , G Pagano ² , M Chazotte ⁵ , K Bestak ⁵ , C Schifflers ¹ , M Iskar ¹ , T Roider ⁶ , F Czernilofsky ⁶ ⁷ ⁸ , P-M Bruch ⁶ , J P Mallm ⁹ , A Cosma ¹⁰ , D E Campton ¹¹ , E Gerhard-Hartmann ¹² , A Rosenwald ¹² , D Colomer ¹³ , E Campo ¹³ , D Schapiro ⁵ ¹⁴ ¹⁵ , E W Green ⁴ , S Dietrich ⁶ , P Lichter ¹ , E Moussay ^# ² , J Paggetti ^# ² , M Zapatka ^# ¹ , M Seiffert ^# ¹⁶

Affiliations

1. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2. Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3. Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany.
4. CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany.
5. Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany.
6. Department of Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
7. European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
8. Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.
9. scOpenLab, German Cancer Research Center, Heidelberg, Germany.
10. National Cytometry Platform, Luxembourg Institute of Health, Luxembourg, Luxembourg.
11. RareCyte, Seattle, WA, USA.
12. Institute for Pathology, University of Würzburg, Würzburg, Germany.
13. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hematopathology Unit, Hospital Clinic, CIBERONC, Barcelona, Spain.
14. Translational Spatial Profiling Center (TSPC), Heidelberg University Hospital, Heidelberg, Germany.
15. Institute of Pathology, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany.
16. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
# Contributed equally.

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 (T_PEX) and terminally exhausted (T_EX) 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.