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

Cid, L. L.; Leong, J. K.; Botana, I. F.; Paul, Y.; Wierz, M.; Floerchinger, A.; Gonder, S.; Pagano, G.; Chazotte, M.; Bestak, K.; Schifflers, C.; Iskar, M.; Roider, T.; Mallm, J.-P.; Cosma, A.; Campton, D. E.; Gerhard-Hartmann, E.; Rosenwald, A.; Colomer, D.; Campo, E.; Shapiro, D.; Dietrich, S.; Lichter, P.; Moussay, E.; Paggetti, J.; Zapatka, M.; Seiffert, M.

doi:10.1101/2022.12.15.519719

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bioRxiv · 10.1101/2022.12.15.519719

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

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Abstract

Failure of cancer immunotherapy is linked to T cell exhaustion. To decipher the underlying mechanisms, we explored the T cell landscape in blood, bone marrow and lymph node samples of patients with chronic lymphocytic leukemia (CLL), and spleen samples of a CLL mouse model. By single-cell RNA-sequencing, mass cytometry (CyTOF), and multiplex image analysis of tissue microarrays, we identified a disease-specific accumulation of distinct regulatory T cell subsets and T cell exhaustion stages and their trajectories in CLL lymph nodes. Integration of T cell receptor sequencing data revealed a clonal expansion of CD8+ precursor exhausted T cells (TPEX), suggesting their CLL reactivity. Interactome analyses identified the TIM3 ligand Galectin-9 as a 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 patients with CLL, renal cell carcinoma or glioma. Statement of significanceOur findings for the first time define the T cell landscape in CLL lymph nodes and reshape the current understanding of T cell exhaustion in this malignancy. They further introduce Galectin-9 as novel immune checkpoint with a high potential to overcome resistance to PD1 targeting drugs in CLL and beyond.

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Cid, L. L., Leong, J. K., Botana, I. F., Paul, Y., Wierz, M., Floerchinger, A., Gonder, S., Pagano, G., Chazotte, M., Bestak, K., Schifflers, C., Iskar, M., Roider, T., Mallm, J.-P., Cosma, A., Campton, D. E., Gerhard-Hartmann, E., Rosenwald, A., Colomer, D., Campo, E., Shapiro, D., Dietrich, S., Lichter, P., Moussay, E., Paggetti, J., Zapatka, M., Seiffert, M.. 2022-12-16. T cell landscape definition by multi-omics identifies Galectin-9 as novel immunotherapy target in chronic lymphocytic leukemia. https://doi.org/10.1101/2022.12.15.519719

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