Clinical roles of TIM-3 in myeloid malignancies and its importance in cellular therapy

Acute myeloid leukemia (AML), one of the most common hematological malignancies worldwide, is derived from a fraction of stem cells known as leukemic stem cells (LSCs), which possess self-renewal and high propagation capacities. Remaining quiescent and being resistant to conventional chemotherapy, residual LSCs after chemotherapy drive leukemia regrowth, leading to AML relapse. Therefore, the eradication of LSCs is critical for the treatment of AML. We previously identified hepatitis A virus cellular receptor 2 (HAVCR2/TIM-3) as an LSC-specific surface molecule by comparing gene expression in LSCs and hematopoietic stem cells (HSCs). TIM-3 expression clearly discriminated LSCs from HSCs within the CD34(+)CD38(−) stem cell fraction. Furthermore, AML cells secrete galectin-9, a TIM-3 ligand, in an autocrine manner, leading to constitutive TIM-3 signaling that maintains the self-renewal capacity of LSCs via the induction of β-catenin accumulation. Thus, TIM-3 is an indispensable functional molecule for human LSCs. Herein, we review the functional aspects of TIM-3 in AML and evaluate minimal/measurable residual disease with a focus on CD34(+)CD38(−)TIM-3(+) LSCs. Using sequential genomic analysis of identical patients, we determined that CD34(+)CD38(−)TIM-3(+) cells in the complete remission (CR) phase after allogeneic stem cell transplantation (allo-SCT) are the LSCs responsible for AML relapse. We retrospectively evaluated the incidence of TIM-3(+) residual LSCs. All analyzed patients achieved CR and complete donor chimerism at the engraftment phase; however, the high frequency of residual TIM-3(+) LSCs within the CD34(+)CD38(−) fraction at engraftment was a significant and independent risk factor for relapse. Residual TIM-3(+) LSC levels in the engraftment phase had a stronger impact on relapse than did pre-SCT disease status. Therefore, the evaluation of residual TIM-3(+) LSCs is a promising approach for predicting leukemia relapse after allo-SCT.