| Autor: |
L Llaó Cid, JKL Wong, I Fernandez Botana, Y Paul, M Wierz, A Flörchinger, S Gonder, G Pagano, M Chazotte, K Bestak, C Schifflers, M Iskar, T Roider, JP Mallm, A Cosma, DE Campton, E Gerhard-Hartmann, A Rosenwald, D Colomer, E Campo, D Schapiro, S Dietrich, P Lichter, E Moussay, J Paggetti, M Zapatka, M Seiffert |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.12.15.519719 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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