Abstract
T-cell immunoglobulin and mucin domain-containing molecule3 (Tim-3) represents a novel mechanism of T-cell dysfunction and exhaustion. Tim-3 has also been identified in various solid tumors. However, the role of Tim-3 expression on blast cells in acute myeloid leukemia (AML) is not well understood. In this study, we aimed to explore the role of Tim-3 in patients with de novo AML, and the correlation between Tim-3 and clinicopathological prognosis. The study cohort consisted of 76 patients with de novo non-M3 AML. These patients’ bone marrow samples were collected and then bone marrow mononuclear cells (BMCs) were isolated for flow cytometry to detect Tim-3 expression on blasts. According to FAB type, 76 diagnosed AML patients included in this study were: M0 (n=2), M1 (n=16), M2 (n=20), M4 (n=20), M5 (n=16), and M6 (n=2). A positive expression (>20%) of Tim-3 was found in 87% (66/76) of patients with AML. The average percentage of Tim-3(+) blasts in these AML patients was 58.26 ± 29.23%. Moreover, the frequency of Tim-3 high expression was higher in M4 patients than that in other AML patients according to FAB type (P=0.004). Tim-3 high expression was also closely associated with inv(16) (P=0.01) and C/EBPA mutation (P=0.03). The mutations of the following six genes, i.e., FLT3-ITD, NPM1, C-KIT, IDH1/IDH2, DNMT3A, were independent of the Tim-3 expression. Additionally, it is more likely to find higher levels of Tim-3 in the low-risk group than in the intermediate- and high-risk groups (P=0.02). The expression of Tim-3 was positively correlated with CD13 (r=0.36, P=0.001), CD34 (r=0.41, P=0.000), and CD7 (r=0.27, P=0.02) in AML patients. AML patients with high Tim-3 expression achieved significantly high complete remission (CR) rate (P=0.01), while their Tim-3 expression significantly decreased after CR (P=0.01). Blockade of Tim-3 expression on AML blasts significantly reduced the Idarubicin (IDA)-mediated suppression of cell growth and reduction of cell apoptosis in vitro. Collectively, our study suggests that high Tim-3 expression on AML blasts could enhances chemotherapy sensitivity.
Highlights
T-cell immunoglobulin and mucin domaincontaining molecule 3 (Tim-3) is a type I membrane protein, which is expressed on Th1 cells, dendritic cells, monocytes and CD8+T cells, and other lymphocyte subsets, mediating immune suppression through different mechanisms [1, 2]
A positive expression (>20%) of Tim-3 was found in 87% (66/76) of patients with acute myeloid leukemia (AML)
T-cell immunoglobulin and mucin domaincontaining molecule 3 (Tim-3) is a membrane protein expressed in various kinds of immune cells and plays a pivotal role in immune regulation [1, 13,14,15]
Summary
T-cell immunoglobulin and mucin domaincontaining molecule 3 (Tim-3) is a type I membrane protein, which is expressed on Th1 cells, dendritic cells, monocytes and CD8+T cells, and other lymphocyte subsets, mediating immune suppression through different mechanisms [1, 2]. Recent studies have focused on the role of Tim-3 expression on CD4+ and CD8+T cells in peripheral blood as well as within tumors. Wu et al showed that Tim-3 expression on CD4+ T cells and CD8+ T cells was elevated in ovarian cancer [3]. It was reported that the coexpression of Tim-3 and PD-1 can be found in the tumor infiltrating lymphocytes of the solid tumor in mice [5]. These studies continue to demonstrate a strong correlation between Tim-3 expression and tumor-associated immune suppression. Whether Tim-3 is expressed on cancer cells, especially myeloid malignant cells, remains an open question. Accumulating studies have revealed the prognostic value of Tim-3 expression as well
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