Abstract
T cell immunoglobulin and mucin domain 3 (TIM-3) expression on malignant cells has been reported in some leukemias. In myelodysplastic syndrome (MDS), increased TIM-3 expression on TH1 cells, regulatory T cells, CD8+ T cells, and hematopoietic stem cells (HSCs), which play a role in the proliferation of blasts and induction of immune escape, has been reported. In AML, several studies have reported overexpression of TIM-3 on leukemia stem cells (LSCs) but not on healthy HSCs. Overexpression of TIM-3 on exhausted CD4+ and CD8+ T cells and leukemic cells in CML, ALL, and CLL patients could be a prognostic risk factor for poor therapeutic response and relapse in patients. Currently, several TIM-3 inhibitors are used in clinical trials for leukemias, and some have shown encouraging response rates for MDS and AML treatment. For AML immunotherapy, blockade TIM-3 may have dual effects: directly inhibiting AML cell proliferation and restoring T cell function. However, blockade of PD-1 and TIM-3 fails to restore the function of exhausted CD8+ T cells in the early clinical stages of CLL, indicating that the effects of TIM-3 blockade may be different in AML and other leukemias. Thus, further studies are required to evaluate the efficacy of TIM-3 inhibitors in different types and stages of leukemia. In this review, we summarize the biological functions of TIM-3 and its contribution as it relates to leukemias. We also discuss the effects of TIM-3 blockade in hematological malignancies and clinical trials of TIM-3 for leukemia therapy.
Highlights
Specialty section: This article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology
We summarize the biological functions of T cell immunoglobulin and mucin domain 3 (TIM-3) and its contribution as it relates to leukemias
This study reported that an upregulated TIM-3 profile is a linked to poor prognostic factors for Chronic lymphocytic leukemia (CLL) patients [77] (Table 1)
Summary
T cell immunoglobulin and mucin domain 3 (TIM-3) is a cell surface molecule which was first identified approximately two decades ago on terminally differentiated CD4+ type 1 helper T cells (TH1 cells) and CD8+ cytotoxic T cells (CTLs) [1]. A study of Jurkat T cells revealed that Tim-3 overexpression following T cell receptor and CD-28 induction promotes Lck or Fyn-dependent phosphorylation of Y256 and Y263. This event leads to accumulation of proteins with SH2 domains, such as the p85 subunit of phosphoinositide 3-kinase (PI3K) and phospholipase C-g1 (PLCg1), to the cytoplasmic tail of TIM-3. Another study of Jurkat cells demonstrated that TCR induction in TIM-3-expressing cells suppresses AP-1 and NFAT activation, resulting in impaired IL-2 production [12,13,14] (Figure 1). HMGB-1 can bind TIM-3 in different contexts and does not always lead to one outcome [18] Another TIM-3 ligand is a well-known “eat-me” signal induction molecule phosphatidylserine (PtdSer). The last ligand is carcinoembryonic antigen cell adhesion molecule 1 (CEACAM-1), which can have both cis and trans interactions with TIM-3 [20]
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