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Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes.

Abstract

T-cell immunoglobulin mucin-3 (Tim-3), an inhibitory immune checkpoint receptor, is highly expressed on acute myeloid leukemia cells and its ligand galectin-9 is reported to drive leukemic progression by binding with Tim-3. However, it remains unclear whether the Tim-3-galectin-9 pathway is associated with the pathophysiology of myelodysplastic syndromes (MDS). Thus, we investigated the expression and function of Tim-3 and the clinical impact of its ligand galectin-9 in MDS. Tim-3 expression levels on MDS blasts by CD45/side-scatter or CD34/CD45 gating were increased as MDS progressed to the advanced stage. Tim-3 expression in the MDS blasts was upregulated in the presence of the cell culture supernatant of human stromal cells or the MDS-related cytokine transforming growth factor-β1. The proliferation of Tim-3+ MDS blasts was inhibited by the blockade of anti-Tim-3 antibody. Furthermore, plasma levels of galectin-9 were elevated as MDS progressed to the advanced stage in 70 MDS/acute leukemia transformed from MDS patients and was a prognostic factor in 40 MDS patients. Our data demonstrated that the Tim-3-galectin-9 pathway is associated with the pathogenesis and disease progression of MDS. These findings provide new insight into potential immunotherapy targeting the galectin-9-Tim-3 pathway in MDS.

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  • Authors+Show Affiliations

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    Department of Hematology, Nippon Medical School, Tokyo, Japan.

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    Department of Hematology, Nippon Medical School, Tokyo, Japan.

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    Department of Hematology, Nippon Medical School, Tokyo, Japan.

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    Department of Hematology, Nippon Medical School, Tokyo, Japan.

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    Department of Hematology, Nippon Medical School, Tokyo, Japan.

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    Department of Hematology, Nippon Medical School, Tokyo, Japan.

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    Department of Hematology, Nippon Medical School, Tokyo, Japan.

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    Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.

    ,

    Department of Hematology, Nippon Medical School, Tokyo, Japan.

    ,

    Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.

    Department of Hematology, Nippon Medical School, Tokyo, Japan.

    Source

    Oncotarget 8:51 2017 Oct 24 pg 88904-88917

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    29179486