Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target
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...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61822-x |
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| author | L. Llaó-Cid JKL Wong I. Fernandez Botana Y. Paul M. Wierz L-M Pilger A. Floerchinger CL Tan S. Gonder G. Pagano M. Chazotte K. Bestak C. Schifflers M. Iskar T. Roider F. Czernilofsky P-M Bruch JP Mallm A. Cosma DE Campton E. Gerhard-Hartmann A. Rosenwald D. Colomer E. Campo D. Schapiro EW Green S. Dietrich P. Lichter E. Moussay J. Paggetti M. Zapatka M. Seiffert |
| author_facet | L. Llaó-Cid JKL Wong I. Fernandez Botana Y. Paul M. Wierz L-M Pilger A. Floerchinger CL Tan S. Gonder G. Pagano M. Chazotte K. Bestak C. Schifflers M. Iskar T. Roider F. Czernilofsky P-M Bruch JP Mallm A. Cosma DE Campton E. Gerhard-Hartmann A. Rosenwald D. Colomer E. Campo D. Schapiro EW Green S. Dietrich P. Lichter E. Moussay J. Paggetti M. Zapatka M. Seiffert |
| author_sort | L. Llaó-Cid |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2d0e4bc9c1704cbfa2fe8403081d26df |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2d0e4bc9c1704cbfa2fe8403081d26df2025-08-20T03:43:10ZengNature PortfolioNature Communications2041-17232025-08-0116112210.1038/s41467-025-61822-xIntegrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy targetL. Llaó-Cid0JKL Wong1I. Fernandez Botana2Y. Paul3M. Wierz4L-M Pilger5A. Floerchinger6CL Tan7S. Gonder8G. Pagano9M. Chazotte10K. Bestak11C. Schifflers12M. Iskar13T. Roider14F. Czernilofsky15P-M Bruch16JP Mallm17A. Cosma18DE Campton19E. Gerhard-Hartmann20A. Rosenwald21D. Colomer22E. Campo23D. Schapiro24EW Green25S. Dietrich26P. Lichter27E. Moussay28J. Paggetti29M. Zapatka30M. Seiffert31Division of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of HealthDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of HealthDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research CenterTumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of HealthTumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of HealthInstitute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University HospitalInstitute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University HospitalDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)Department of Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital HeidelbergDepartment of Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital HeidelbergDepartment of Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital HeidelbergscOpenLab, German Cancer Research CenterNational Cytometry Platform, Luxembourg Institute of HealthRareCyteInstitute for Pathology, University of WürzburgInstitute for Pathology, University of WürzburgInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hematopathology Unit, Hospital Clinic, CIBERONCInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hematopathology Unit, Hospital Clinic, CIBERONCInstitute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University HospitalCCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research CenterDepartment of Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital HeidelbergDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of HealthTumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of HealthDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)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.https://doi.org/10.1038/s41467-025-61822-x |
| spellingShingle | L. Llaó-Cid JKL Wong I. Fernandez Botana Y. Paul M. Wierz L-M Pilger A. Floerchinger CL Tan S. Gonder G. Pagano M. Chazotte K. Bestak C. Schifflers M. Iskar T. Roider F. Czernilofsky P-M Bruch JP Mallm A. Cosma DE Campton E. Gerhard-Hartmann A. Rosenwald D. Colomer E. Campo D. Schapiro EW Green S. Dietrich P. Lichter E. Moussay J. Paggetti M. Zapatka M. Seiffert Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target Nature Communications |
| title | Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target |
| title_full | Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target |
| title_fullStr | Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target |
| title_full_unstemmed | Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target |
| title_short | Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target |
| title_sort | integrative multi omics reveals a regulatory and exhausted t cell landscape in cll and identifies galectin 9 as an immunotherapy target |
| url | https://doi.org/10.1038/s41467-025-61822-x |
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