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

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

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. m.seiffert@dkfz.de.
  • # Contributed equally.
PMID: 40775219 DOI: 10.1038/s41467-025-61822-x
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.

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