At least four ligands for Tim-3 have been identified, i.e., galectin-9, high mobility group box 1 (HMGB-1), Ceacam-1, and phosphatidylserine. T-cell immunoglobulin mucin-3 (Tim-3), an immune checkpoint receptor, is expressed on CD4 +, CD8 +, and regulatory T cells and other immune cells such as monocytes, dendritic cells, and natural killer cells and inhibits T cell proliferation in antitumor immunity. The suppression of antitumor immunity such as PD-L1 upregulation on MDS blasts may be associated with AML progression. During disease progression, some gene mutations tend to be newly acquired. In progression to advanced disease, clonal blasts gain aggressive behavior with more proliferative potential and fewer apoptotic cells compared with those in patients with low-grade disease. Thus, it is crucial to elucidate the mechanism of disease progression and leukemic transformation in MDS patients. Acute leukemia transformed from MDS (AL-MDS) occurs in 10–40% of MDS patients, and those patients had poor prognosis with a median survival time of 4.7 months. Myelodysplastic syndromes (MDS) are clonal hematologic stem cell disorders characterized by cytopenia and a high risk of progression to acute myeloid leukemia (AML). These findings provide new insight into potential immunotherapy targeting the galectin-9–Tim-3 pathway in MDS. Our data demonstrated that the Tim-3-galectin-9 pathway is associated with the pathogenesis and disease progression of MDS. 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. The proliferation of Tim-3 + MDS blasts was inhibited by the blockade of anti-Tim-3 antibody. 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. Tim-3 expression levels on MDS blasts by CD45/side-scatter or CD34/CD45 gating were increased as MDS progressed to the advanced stage. Thus, we investigated the expression and function of Tim-3 and the clinical impact of its ligand galectin-9 in MDS. However, it remains unclear whether the Tim-3–galectin-9 pathway is associated with the pathophysiology of myelodysplastic syndromes (MDS). 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.
Received: JanuAccepted: AugPublished: October 04, 2017 Keywords: myelodysplastic syndromes, Tim-3, galectin-9, acute leukemia, immune checkpoint molecule
Toshio Asayama 1, Hideto Tamura 1, Mariko Ishibashi 1, Yasuko Kuribayashi-Hamada 1, Asaka Onodera-Kondo 1, Namiko Okuyama 1, Akiko Yamada 1, Masumi Shimizu 2, Keiichi Moriya 1, Hidemi Takahashi 2 and Koiti Inokuchi 1ġDepartment of Hematology, Nippon Medical School, Tokyo, JapanĢDepartment of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan
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