Integrative multi-omics identifies regulatory and exhausted T cell types and novel immunotherapy targets in CLL lymph nodes
Abstract 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) using 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 their differentiation state trajectories. In comparison to blood and bone marrow where T cell phenotypes were similar, T cells in CLL lymph nodes were most distinct. We identified a disease-specific accumulation of regulatory T cell subsets and CD8+ T cells harboring different stages of exhaustion, including precursor exhausted T cells (TPEX) and terminally exhausted (TEX) exclusively in the CLL lymph node tissue. Integration of T cell receptor sequencing data revealed a clonal expansion of TPEX, suggesting their reactivity for CLL cells. Interactome analyses identified novel potential immunotherapy targets for CLL, including the TIM3 ligand Galectin-9. Targeting Galectin-9 slowed down disease development and reduced the number of TIM3 expressing T cells in a CLL mouse model. Galectin-9 expression correlated with shorter survival of patients with CLL, renal cell carcinoma or glioma. It therefore likely contributes to cancer immune escape and represents a novel target for immunotherapy..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
ResearchSquare.com - (2024) vom: 29. März Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Seiffert, Martina [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.21203/rs.3.rs-3909204/v1 |
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| 520 | |a Abstract 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) using 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 their differentiation state trajectories. In comparison to blood and bone marrow where T cell phenotypes were similar, T cells in CLL lymph nodes were most distinct. We identified a disease-specific accumulation of regulatory T cell subsets and CD8+ T cells harboring different stages of exhaustion, including precursor exhausted T cells (TPEX) and terminally exhausted (TEX) exclusively in the CLL lymph node tissue. Integration of T cell receptor sequencing data revealed a clonal expansion of TPEX, suggesting their reactivity for CLL cells. Interactome analyses identified novel potential immunotherapy targets for CLL, including the TIM3 ligand Galectin-9. Targeting Galectin-9 slowed down disease development and reduced the number of TIM3 expressing T cells in a CLL mouse model. Galectin-9 expression correlated with shorter survival of patients with CLL, renal cell carcinoma or glioma. It therefore likely contributes to cancer immune escape and represents a novel target for immunotherapy. | ||
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