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

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) 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE221395 | GEO | 2023/11/23

REPOSITORIES: GEO

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Project description:The goal of this study was to examine differences in gene expression of tumor specific CD8 T cells in an in vivo tumor mouse model after inhibition of galectin-3 protein expression by genetic knockout. Galectin-3 is thought to modulate CD8 T cell response by cross-linking cell surface glycoproteins Galectin-3 is a 31 kD carbohydrate-binding lectin that is over-expressed by many human malignancies. It also modulates T cell responses through a diverse array of mechanisms including induction of apoptosis, TCR cross linking in CD8+ T cells, and T cell receptor (TCR) down regulation in CD4+ T cells. We found that patients responding to a granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting allogeneic pancreatic tumor vaccine developed post immunization antibody responses to galectin-3 on a proteomic screen. We used the HER-2/neu (neu-N) transgenic mouse model to study galectin-3 binding on adoptively transferred high avidity neu-specific CD8+ T cells derived from TCR transgenic mice. Here, we show that galectin-3 binds preferentially to activated antigen-committed CD8+ T cells only in the tumor microenvironment (TME). Galectin-3 deficient mice exhibit improved CD8+ T cell effector function and increased expression of several inflammatory genes when compared with wild type (WT) mice. We also show that galectin-3 binds to LAG-3, and LAG-3 expression is necessary for galectin-3 mediated suppression of CD8+ T cells in vitro. Lastly, galectin-3 deficient mice have significantly elevated levels of circulating plasmacytoid dendritic cells (pDCs), which are superior to conventional dendritic cells (cDCs) in activating CD8+ T cells. Binding of galectin-3 to cell-surface glycoproteins on immune cells suppresses a pro-inflammatory immune response. Thus, inhibiting galectin-3 in conjunction with CD8+ T cell directed immunotherapies should enhance the tumor specific immune response. 3 different experimental groups were studied. Galectin-3 WT CD8 T cells adoptively transferred into Galectin-3 WT mice, galectin-3 WT CD8 T cells transferred into galectin-3 KO mice, and finally galectin-3 KO CD8 T cells transferred into galectin-3 KO mice. Galectin-3 WT CD8 T cells transferred into Galectin-3 WT mice were used as the reference group. Four biological replicates were submitted for each group, and adoptively transfered CD8 T cells were isolated 5 days post-adoptive transfer into tumor-bearing mice treated with a whole cell GM-CSF secreting vaccine. Cells were purified by cell sorting on the Thy1.2 surface marker.

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

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