TIM3 expression by leukemic and non‐leukemic myeloblasts

Background: Acute lymphoblastic leukemia (ALL) is a malignancy with aggressive tumors of immature lymphocytes. T-cell immunoglobulin and mucin-domain 3 (TIM-3) is a Type I transmembrane glycoprotein which is involved in cell proliferation. The objective of this research is to determine the TIM-3 expression in peripheral blood (PB) and bone marrow (BM) of 80 samples of normal and ALL patients. Materials and Methods: The amount of mRNA and protein of TIM-3 measured in the BM and PB the mononuclear layer of samples by real-time polymerase chain reaction and Western blotting. Results: Our findings indicated that relative mRNA expression of TIM-3 in PB and BM of the mononuclear layer of ALL patients was 1.7 and 5 times higher than normals, respectively. We also reported that the protein level of TIM-3 in mononuclear cells of ALL patients was 3.2-fold in BM and two-fold in PB more than normals. Conclusion: In conclusion, this study shows that TIM-3 increases in ALL patients, thus the expression of TIM-3 in tumor cells may be considered as a potential predictive factor in ALL patients, which needs to be explored in future.

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“…[ 11 29 ] Interestingly, TIM-3 has not existed in CD34 + CD38 − normal HSCs and CD34 + CD38 + normal progenitor cells. [ 11 30 ]…”

Section: Discussionmentioning

confidence: 99%

Study of T-cell immunoglobulin and mucin domain-3 expression profile in peripheral blood and bone marrow of human acute lymphoblastic leukemia patients

et al. 2020

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“…Additionally, Tim-3 was described as an AML stem cell (LSC) antigen, and its ligand galectin-9 (Gal-9) works in an autocrine loop contributing to LSC self-renewal. Moreover, Tim-3 as a trafficker for the secretion of Gal-9 may contribute to AML development [25,26]. This finding may indicate one of the reasons for the anti-cancer T cell activity impairment in AML.…”

Section: Introductionmentioning

confidence: 94%

Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML

Tan

Huang

et al. 2020

Biomark Res

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Background: Altered expression of T cell immune inhibitory receptors may result in immunosuppression and associate with the poor prognosis of leukemia patients in which the leukemic bone marrow (BM) microenvironment may contribute to such immunosuppression. We found higher numbers of programmed death-1 (PD-1) + exhausted T cells in peripheral blood (PB) from acute myeloid leukemia (AML) patients. To investigate the leukemic BM influence on immunosuppression, we further compared the distributions of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) and the exhausted T cell phenotype in PB and BM from AML patients and characterized their relationship with clinical outcome. Methods: PB and BM samples from 15 patients with newly diagnosed AML were collected and analyzed for the expression of PD-1, Tim-3, CD244, and CD57 on CD3+, CD4+, and CD8+ T cells by multicolor flow cytometry. Results: The proportions of PD-1 + CD3+ and PD-1 + CD8+ T cells were significantly higher in BM compared with PB. Similarly, higher PD-1 + CD244 + CD3+ and PD-1 + CD244 + CD8+ T cells were found in BM, and an increased tendency for PD-1 + CD244 + CD4+ T cells was also detected in this group. In contrast, increased Tim-3 + CD4+/ Tim-3 + CD244 + CD4+ T cells were predominant in BM compared with PB, but there was no statistically significant difference in Tim-3 + CD8+ T cells. Moreover, PD-1 and Tim-3 double-positive CD3+/CD4+/CD8+ T cells were significantly increased in the BM group. In addition, a higher proportion of PD-1 + Tim-3 + CD3+ T cells in the BM and PD-1 + Tim-3 + CD4+ T cells in PB was detected in non-complete remission (NCR) compared with complete remission (CR) patients after first-cycle chemotherapy. Conclusions: Upregulation of PD-1 and Tim-3 and the exhausted phenotype of CD4+ and CD8+ T cells in the BM of AML patients may contribute to mediating the leukemic immunosuppressive microenvironment, and increased PD-1 + Tim-3+ CD8+ T cells may be related to T cell dysfunction in AML, which may influence clinical outcome.

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“…In addition to PD-1 and CTLA-4 there are several other inhibitory immune checkpoints that can be therapeutically targeted to enhance the host's immune response to malignant cells. Tcell immunoglobulin mucin-3 (TIM-3) is a glycoprotein that is expressed on the surface of regulatory T-cells, INF-γ producing T-cells, and innate immune cells and has been shown to be expressed at increased levels on AML and leukemic stem cells [91][92][93] . The effect of TIM-3 activation is context-dependent and includes both inhibition of T-cell-mediated immune responses and pro-inflammatory effects by activation of macrophages 94,95 .…”

Section: 1) Tim-3 and Lag-3mentioning

confidence: 99%

Immune checkpoint-based therapy in myeloid malignancies: a promise yet to be fulfilled

Bewersdorf

Stahl

Zeidan

2019

Expert Review of Anticancer Therapy

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Introduction: Immune system evasion is essential for tumor cell survival and is mediated by the immunosuppressive tumor microenvironment and the activation of inhibitory immune checkpoints. While immune checkpoint-based therapy yielded impressive results in several advanced solid malignancies such as melanoma and non-small cell lung cancer, its role in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is still evolving. Areas covered: Here we review the immunology in the tumor microenvironment in the bone marrow and discuss the current preclinical and clinical data for immune checkpoint-based therapy in myeloid neoplasms. Expert opinion: Clinical trials of immune checkpoint inhibitors (ICI) in AML and MDS are still in early stages and reported results so far have been modest especially for monotherapy use in the refractory settings. However, there are preliminary data for synergistic effects for combination of multiple ICI with hypomethylating agents and conventional chemotherapy. ICI might also be effective in eradicating minimal residual disease and to prevent relapse following induction chemotherapy or hematopoietic stem cell transplant. Additional trials to provide insight into the efficacy and safety profile of immune checkpoint-based therapy, its optimal timing and potential combination with other types of therapy as well as identification of predictive biomarkers are needed.

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TIM3 expression by leukemic and non‐leukemic myeloblasts

Cited by 21 publications

References 17 publications

Study of T-cell immunoglobulin and mucin domain-3 expression profile in peripheral blood and bone marrow of human acute lymphoblastic leukemia patients

Study of T-cell immunoglobulin and mucin domain-3 expression profile in peripheral blood and bone marrow of human acute lymphoblastic leukemia patients

Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML

Immune checkpoint-based therapy in myeloid malignancies: a promise yet to be fulfilled

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