High Tim-3 expression on AML blasts could enhance chemotherapy sensitivity

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.

Expression of immune check point gene TIM‑3 in patients newly diagnosed with acute myeloid leukemia: Significance and impact on outcome

“…The results demonstrated that TIM-3 expression was significantly upregulated in patients with AML compared with that in the control group. This result is consistent with previous findings, which have demonstrated that TIM-3 expression is upregulated in bone marrow samples of patients with AML via RT-qPCR analysis ( 25 ) and flow cytometric analysis of peripheral blood T cells or bone marrow blasts ( 13 , 26 ). The results of the present study also demonstrated that TIM-3 expression exhibited moderate diagnostic value in the AML cohort.…”

“…The present study detected significantly higher TIM-3 expression in patients with positive expression of surface antigens CD34, CD13 and HLA-DR, which are considered predictors of adverse outcome in AML ( 30 , 31 ). These results are consistent with those in the study by Xu et al ( 26 ), which detected significantly positive correlations between TIM-3 expression and CD34 and CD13 in patients with AML. Several studies have reported that patients with AML and EMD have a worse prognosis due to a poor response to chemotherapy and a high relapse rate ( 32 ).…”

“…Cytogenetics analysis is one of the most powerful independent prognostic factors in AML; however, comparisons between TIM-3 expression in different cytogenetic risk categories in the present study failed to prove any association between cytogenetic risk groups and high TIM-3 expression. Conversely, Xu et al ( 26 ) confirmed a significant association between TIM-3 expression and inv(16), which is a favorable cytogenetic abnormality, while Li et al ( 13 ) reported that high TIM-3 expression on CD8 + T cells in patients with AML is significantly associated with unfavorable cytogenetic abnormalities. The present study detected significantly higher TIM-3 expression in patients with positive expression of surface antigens CD34, CD13 and HLA-DR, which are considered predictors of adverse outcome in AML ( 30 , 31 ).…”

Pre-transplant sTIM-3 levels may have a predictive impact on transplant outcome in acute leukemia patients

“…Elevated sTIM-3 levels in AML patients are compatible with the previous reports which indicate a prominent effect of TIM-3 in AML pathophysiology and prognosis as TIM-3 is identified as an AML LSCspecific surface molecule [14,44,45]. TIM-3 and galectin-9 complex induces the activation of the NF-κB and β-catenin signalling which promotes gene expression modifications leading to improved LSC survival [45].…”

“…Expression level of TIM-3 was found to be higher in immature AML cells with core binding factor translocations. As TIM-3 levels were higher in the low-risk group than intermediate and high risk groups, patients with high TIM-3 expression represented significantly higher complete remission rates [44]. Although our study seems to confirm the association of the protein with cytogenetics, detailed statistical analysis on specific cytogenetic features, which may elucidate the particular point of the linkage, could not be performed due to the limited number of patients.…”