TY  - JOUR
AU  - Llaó-Cid, L.
AU  - Wong, Jkl
AU  - Fernandez Botana, I.
AU  - Paul, Y.
AU  - Wierz, M.
AU  - Pilger, L-M
AU  - Floerchinger, A.
AU  - Tan, Chin Leng
AU  - Gonder, S.
AU  - Pagano, G.
AU  - Chazotte, M.
AU  - Bestak, K.
AU  - Schifflers, Christoph
AU  - Iskar, Murat
AU  - Roider, T.
AU  - Czernilofsky, F.
AU  - Bruch, P-M
AU  - Mallm, J. P.
AU  - Cosma, A.
AU  - Campton, D. E.
AU  - Gerhard-Hartmann, E.
AU  - Rosenwald, A.
AU  - Colomer, D.
AU  - Campo, E.
AU  - Schapiro, D.
AU  - Green, Edward
AU  - Dietrich, S.
AU  - Lichter, P.
AU  - Moussay, E.
AU  - Paggetti, J.
AU  - Zapatka, Marc
AU  - Seiffert, Martina
TI  - Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-01646
SP  - 7271
PY  - 2025
N1  - #EA:B060#LA:B060#
AB  - 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.
KW  - Galectins: metabolism
KW  - Galectins: genetics
KW  - Galectins: antagonists & inhibitors
KW  - Galectins: immunology
KW  - Leukemia, Lymphocytic, Chronic, B-Cell: immunology
KW  - Leukemia, Lymphocytic, Chronic, B-Cell: therapy
KW  - Leukemia, Lymphocytic, Chronic, B-Cell: genetics
KW  - Leukemia, Lymphocytic, Chronic, B-Cell: pathology
KW  - Humans
KW  - Animals
KW  - Mice
KW  - Hepatitis A Virus Cellular Receptor 2: metabolism
KW  - Immunotherapy: methods
KW  - T-Lymphocytes, Regulatory: immunology
KW  - T-Lymphocytes, Regulatory: metabolism
KW  - Lymph Nodes: immunology
KW  - Lymph Nodes: pathology
KW  - CD8-Positive T-Lymphocytes: immunology
KW  - CD8-Positive T-Lymphocytes: metabolism
KW  - Female
KW  - Male
KW  - Disease Models, Animal
KW  - Multiomics
KW  - Galectins (NLM Chemicals)
KW  - LGALS9 protein, human (NLM Chemicals)
KW  - Hepatitis A Virus Cellular Receptor 2 (NLM Chemicals)
KW  - galectin 9, mouse (NLM Chemicals)
KW  - HAVCR2 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40775219
DO  - DOI:10.1038/s41467-025-61822-x
UR  - https://inrepo02.dkfz.de/record/303421
ER  -