TIM-3 in Leukemia; Immune Response and Beyond

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.

Keywords: TIM-3; acute lymphoblastic leukemia; acute myeloid leukemia; chronic lymphoblastic leukemia; chronic myeloid leukemia; myelodysplastic syndrome.

Figure 1

TIM-3 signaling in T cells in the presence (A) and absence (B) of galectin-9. In the absence of Gal-9, Bat3 binds to tyrosine residues in the cytoplasmic tail of TIM-3 (Y256 and Y263 in mice and Y26 and Y272 humans). This process leads to accumulation of the active form of Lck, which promotes phosphorylation of Zap70 and T cell signaling when the MHC peptide-TCR complex is formed. In the presence of Gal-9, as the ligand for TIM-3, phosphorylation of the tyrosine residues results in Bat3 release from the cytoplasmic tail. In this paradigm, Bat3 cannot form a complex with Lck; thus, TIM-3 induction inhibits T cell signaling. TIM-3, T cell immunoglobulin and mucin domain-3; Gal-9, galectin-9; Bat3, HLA-B associated transcript 3; TCR, T cell receptor; ITAM, immunoreceptor tyrosine-based activation motif; APC, antigen presenting cell; MHC, major histocompatibility complex; Ag, antigen. The figure was produced with the assistance of Servier Medical Art (https://smart.servier.com).

Figure 2

Schematic diagram of TIM-3 identification, TIM-3 inhibitor development, and TIM-3 blockade in cancer and leukemia therapies in clinical trials.