T cell landscape definition by multi-omics identifies Galectin-9 as novel immunotherapy target in chronic lymphocytic leukemia

Failure of immunotherapy after applying checkpoint inhibitors or CAR-T cells is linked to T cell exhaustion. Here, we explored the T cell landscape in chronic lymphocytic leukemia (CLL) by single-cell omics analyses of blood, bone marrow and lymph node samples of patients and spleen samples of a CLL...

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Published inbioRxiv
Main Authors Laura Llao Cid, Leong, John Kwong, Iria Fernandez Botana, Yashna, Paul, Wierz, Marina, Floerchinger, Alessia, Gonder, Susanne, Pagano, Giulia, Chazotte, Margot, Bestak, Kresimir, Schifflers, Christoph, Iskar, Murat, Roider, Tobias, Jan-Philipp Mallm, Cosma, Antonio, Campton, D E, Gerhard-Hartmann, E, Rosenwald, Andreas, Colomer, D, Campo, E, Shapiro, Denis, Dietrich, Sascha, Lichter, Peter, Moussay, Etienne, Paggetti, Jerome, Zapatka, Marc, Seiffert, Martina
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 16.12.2022
Subjects
Bone marrow
CD8 antigen
Cell differentiation
Chronic lymphocytic leukemia
Cytometry
Galectin-9
Image processing
Immune checkpoint inhibitors
Immunoregulation
Immunotherapy
Leukemia
Lymph nodes
Lymphatic system
Lymphocytes
Lymphocytes T
Phenotypes
T cell receptors
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Summary:Failure of immunotherapy after applying checkpoint inhibitors or CAR-T cells is linked to T cell exhaustion. Here, we explored the T cell landscape in chronic lymphocytic leukemia (CLL) by single-cell omics analyses of blood, bone marrow and lymph node samples of patients and spleen samples of a CLL mouse model. By single-cell RNA-sequencing, mass cytometry (CyTOF), and multiplex image analysis of tissue microarrays, we defined the spectrum of phenotypes and transcriptional programs of T cells and and their differentiation state trajectories. We identified disease-specific accumulation of distinct regulatory T cell subsets and T cells harboring an exhausted phenotype exclusively in the CLL lymph node tissue. Integration of TCR data revealed a clonal expansion of CD8+ precursor exhausted T cells, suggesting their reactivity for CLL cells. Interactome analyses identified the TIM3 ligand Galectin-9 as novel immunoregulatory molecule in CLL. Blocking of Galectin-9 in CLL-bearing mice slowed down disease development and reduced the number of TIM3 expressing T cells. Galectin-9 expression correlated with shorter survival of CLL patients. Thus, Galectin-9 contributes to immune escape in CLL and represents a novel target for immunotherapy.Competing Interest StatementD.S. reports funding from GSK.
DOI:10.1101/2022.12.15.519719