The TIM3/Gal9 signaling pathway: An emerging target for cancer immunotherapy

Kandel, Sashi; Adhikary, Pratik; Li, Guangfu; Cheng, Kun

doi:10.1016/j.canlet.2021.04.011

Cited by 87 publications

(62 citation statements)

References 132 publications

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“…Among them, Gal-9 and CEACAM1 are involved in TIM-3 mediating the inhibition and apoptosis of T cells ( 7 ). TIM-3 is a glycoprotein containing both N-linked and O-linked glycans, and glycosylation is required for Gal-9 binding ( 21 , 22 ).…”

Section: Discussionmentioning

confidence: 99%

TIM-3 Expression Level on AML Blasts Correlates With Presence of Core Binding Factor Translocations Rather Than Clinical Outcomes

Xia

Huang

et al. 2022

Front. Oncol.

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BackgroundT-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) expresses on leukemic stem and progenitor populations of non-M3 acute myeloid leukemia (AML) as well as T lymphocytes. TIM-3 is thought to be involved in the self-renewal of leukemic stem cells and the immune escape of AML cells, however its correlation with AML prognosis is still controversial and worthy of further investigation.Methodswe simultaneously assessed TIM-3 expression levels of leukemic blasts and T lymphocytes in the bone marrow of de novo AML patients using flow cytometry. The correlations of TIM-3 expression between leukemic blasts and T lymphocytes and the correlations of TIM-3 expression with various patient parameters were analyzed. In addition, the Cancer Genome Atlas (TCGA) data of AML patients were acquired and analyzed to verify the results.ResultsTIM-3 expression of CD34+ leukemic blasts (R2 = 0.95, p<0.0001) and CD34+CD38- leukemic stem cells (R2 = 0.75, p<0.0001) were significantly and positively correlated with that of the whole population of leukemic blasts. In addition, TIM-3 expression level of leukemic blasts correlated significantly and positively with that of CD8+ (R2 = 0.44, p<0.0001) and CD4+ (R2 = 0.16, p=0.0181) lymphocytes, and higher TIM-3 expression of leukemic blasts was significantly associated with a greater proportion of peripheral CD8+ T lymphocytes (R2 = 0.24, p=0.0092), indicating that TIM-3 on leukemic blasts might alter adaptive immunity of AML patients. Regarding clinical data, the presence of core binding factor (CBF) translocations was significantly correlated with higher TIM-3 expression of leukemic blasts (CBF versus non-CBF, median 22.78% versus 1.28%, p=0.0012), while TIM-3 expression levels of leukemic blasts were not significantly associated with the remission status after induction chemotherapy (p=0.9799), overall survival (p=0.4201) or event-free survival (p=0.9873). Similar to our results, TCGA data showed that patients with CBF translocations had significantly higher mRNA expression level of HAVCR2 (the gene encoding TIM-3) (median, 9.81 versus 8.69, p<0.0001), and as all patients in the cohort were divided into two groups based on the median HAVCR2 expression level, 5-year overall survivals were not significantly different (low versus high, 24.95% versus 24.54%, p=0.6660).ConclusionTIM-3 expression level on AML blasts correlates with presence of CBF translocations rather than clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

TIM-3 Expression Level on AML Blasts Correlates With Presence of Core Binding Factor Translocations Rather Than Clinical Outcomes

Xia

Huang

et al. 2022

Front. Oncol.

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“…A key inhibitor molecule for tumour T cells is the TIM‐3 89 . TIM‐3 is not constitutively expressed on Tregs; however, it is highly expressed within TME due to the constant stimulation of tumour‐associated antigens.…”

Section: Combination Therapy Of Pd‐1/pd‐l1 Inhibitors and Treg‐modula...mentioning

confidence: 99%

Targeting regulatory T cells in anti‐PD‐1/PD‐L1 cancer immunotherapy

Zhulai

Олейник

2022

Scand J Immunol

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The programmed death (PD)‐1/PD‐ligand (PD‐L) pathway and regulatory T cells (Tregs) are essential for the maintenance of immune tolerance. Their activation in the tumour microenvironment contributes to the evasion of the transformed cells from the immune surveillance and the suppression of an antitumour immune response. Therefore, PD‐1/PD‐L1 and Tregs are important targets for cancer immunotherapy. Our review focuses on the current role of the PD‐1/PD‐L1 axis in Treg development and function in the tumour microenvironment. We also discuss combination therapy with PD‐1/PD‐L1 inhibitors and Treg‐modulating agents affecting the adenosinergic pathway, TGF‐β signalling, immune checkpoints and other approaches to downregulation of Tregs.

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“…Expressed on T cells the TIM-3/Gal-9 interaction leads to weakening of the Th1-mediated immunity and apoptosis of T cells which results in an inhibition of the immune system. On the other hand, when expressed on NK cells and dendritic cells the binding of Gal-9 results in an immunostimulatory effect [35].…”

Section: The Tim-3/gal-9 System In Normal Pregnancymentioning

confidence: 99%

The Role of the Immune Checkpoint Molecules PD-1/PD-L1 and TIM-3/Gal-9 in the Pathogenesis of Preeclampsia—A Narrative Review

et al. 2022

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Preeclampsia is a pregnancy-specific disease which is characterized by abnormal placentation, endothelial dysfunction, and systemic inflammation. Several studies have shown that the maternal immune system, which is crucial for maintaining the pregnancy by ensuring maternal-fetal-tolerance, is disrupted in preeclamptic patients. Besides different immune cells, immune checkpoint molecules such as the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1 system) and the T-cell immunoglobulin and mucin domain-containing protein 3/Galectin-9 (TIM-3/Gal-9 system) are key players in upholding the balance between pro-inflammatory and anti-inflammatory signals. Therefore, a clear understanding about the role of these immune checkpoint molecules in preeclampsia is essential. This review discusses the role of these two immune checkpoint systems in pregnancy and their alterations in preeclampsia.

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The TIM3/Gal9 signaling pathway: An emerging target for cancer immunotherapy

Cited by 87 publications

References 132 publications

TIM-3 Expression Level on AML Blasts Correlates With Presence of Core Binding Factor Translocations Rather Than Clinical Outcomes

TIM-3 Expression Level on AML Blasts Correlates With Presence of Core Binding Factor Translocations Rather Than Clinical Outcomes

Targeting regulatory T cells in anti‐PD‐1/PD‐L1 cancer immunotherapy

The Role of the Immune Checkpoint Molecules PD-1/PD-L1 and TIM-3/Gal-9 in the Pathogenesis of Preeclampsia—A Narrative Review

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