%0 Journal Article
%A Llaó-Cid, L.
%A Wong, Jkl
%A Fernandez Botana, I.
%A Paul, Y.
%A Wierz, M.
%A Pilger, L-M
%A Floerchinger, A.
%A Tan, Chin Leng
%A Gonder, S.
%A Pagano, G.
%A Chazotte, M.
%A Bestak, K.
%A Schifflers, Christoph
%A Iskar, Murat
%A Roider, T.
%A Czernilofsky, F.
%A Bruch, P-M
%A Mallm, J. P.
%A Cosma, A.
%A Campton, D. E.
%A Gerhard-Hartmann, E.
%A Rosenwald, A.
%A Colomer, D.
%A Campo, E.
%A Schapiro, D.
%A Green, Edward
%A Dietrich, S.
%A Lichter, P.
%A Moussay, E.
%A Paggetti, J.
%A Zapatka, Marc
%A Seiffert, Martina
%T Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target.
%J Nature Communications
%V 16
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DKFZ-2025-01646
%P 7271
%D 2025
%Z #EA:B060#LA:B060#
%X 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.
%K Galectins: metabolism
%K Galectins: genetics
%K Galectins: antagonists & inhibitors
%K Galectins: immunology
%K Leukemia, Lymphocytic, Chronic, B-Cell: immunology
%K Leukemia, Lymphocytic, Chronic, B-Cell: therapy
%K Leukemia, Lymphocytic, Chronic, B-Cell: genetics
%K Leukemia, Lymphocytic, Chronic, B-Cell: pathology
%K Humans
%K Animals
%K Mice
%K Hepatitis A Virus Cellular Receptor 2: metabolism
%K Immunotherapy: methods
%K T-Lymphocytes, Regulatory: immunology
%K T-Lymphocytes, Regulatory: metabolism
%K Lymph Nodes: immunology
%K Lymph Nodes: pathology
%K CD8-Positive T-Lymphocytes: immunology
%K CD8-Positive T-Lymphocytes: metabolism
%K Female
%K Male
%K Disease Models, Animal
%K Multiomics
%K Galectins (NLM Chemicals)
%K LGALS9 protein, human (NLM Chemicals)
%K Hepatitis A Virus Cellular Receptor 2 (NLM Chemicals)
%K galectin 9, mouse (NLM Chemicals)
%K HAVCR2 protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40775219
%R 10.1038/s41467-025-61822-x
%U https://inrepo02.dkfz.de/record/303421