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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

    ,

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

    ,

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

    ,

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

    ,

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

    ,

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

    ,

    Department of Hematology, 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.

    ,

    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

    Citation

    TY - JOUR T1 - Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes. AU - Asayama,Toshio, AU - Tamura,Hideto, AU - Ishibashi,Mariko, AU - Kuribayashi-Hamada,Yasuko, AU - Onodera-Kondo,Asaka, AU - Okuyama,Namiko, AU - Yamada,Akiko, AU - Shimizu,Masumi, AU - Moriya,Keiichi, AU - Takahashi,Hidemi, AU - Inokuchi,Koiti, Y1 - 2017/10/04/ PY - 2017/01/24/received PY - 2017/08/23/accepted PY - 2017/11/29/entrez KW - Tim-3 KW - acute leukemia KW - galectin-9 KW - immune checkpoint molecule KW - myelodysplastic syndromes SP - 88904 EP - 88917 JF - Oncotarget JO - Oncotarget VL - 8 IS - 51 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/29179486/Functional_expression_of_Tim-3_on_blasts_and_clinical_impact_of_its_ligand_galectin-9_in_myelodysplastic_syndromes. ER -