Oncotarget

Research Papers:

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

Toshio Asayama, Hideto Tamura _, Mariko Ishibashi, Yasuko Kuribayashi-Hamada, Asaka Onodera-Kondo, Namiko Okuyama, Akiko Yamada, Masumi Shimizu, Keiichi Moriya, Hidemi Takahashi and Koiti Inokuchi

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Oncotarget. 2017; 8:88904-88917. https://doi.org/10.18632/oncotarget.21492

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Abstract

Toshio Asayama1, Hideto Tamura1, Mariko Ishibashi1, Yasuko Kuribayashi-Hamada1, Asaka Onodera-Kondo1, Namiko Okuyama1, Akiko Yamada1, Masumi Shimizu2, Keiichi Moriya1, Hidemi Takahashi2 and Koiti Inokuchi1

1Department of Hematology, Nippon Medical School, Tokyo, Japan

2Department 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.


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