Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target
- 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
2025-08-07
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.