Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target
Abstract
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.
Article Details
Authors (32)
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