Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target
Laura Llaó Cid, Jkl Wong, Iria Fernandez Botana, Yashna Paul, Marina Wierz, L-M Pilger, Alessia Floerchinger, Chin Leng Tan, Susanne Gonder, Giulia Pagano, Margot Chazotte, Kresimir Bestak, Christoph Schifflers, Murat Iskar, Tobias Roider, Felix Czernilofsky, Peter‐Martin Bruch, Jan‐Philipp Mallm, Antonio Cosma, Daniel Campton, Elena Hartmann, Andreas Rosenwald, Dolors Colomer, Elı́as Campo, Denis Schapiro, Edward W. Green, Sascha Dietrich, Peter Lichter, Etienne Moussay, Jérôme Paggetti, Marc Zapatka, Martina Seiffert
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 (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.