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<p>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<sup>+</sup> T cells in various exhaustion states, including precursor (T<sub>PEX</sub>) and terminally exhausted (T<sub>EX</sub>) 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<sup>+</sup> 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.</p>

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Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月7日

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  • 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

摘要

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.