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

// 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 1 1 Department of Hematology, Nippon Medical School, Tokyo, Japan 2 Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan Correspondence to: Hideto Tamura, e-mail: tam@nms.ac.jp Keywords: myelodysplastic syndromes, Tim-3, galectin-9, acute leukemia, immune checkpoint molecule Received: January 24, 2017 Accepted: August 23, 2017 Published: October 04, 2017 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.