TIM‐3 in normal and malignant hematopoiesis: Structure, function, and signaling pathways

Kikushige, Yoshikane

doi:10.1111/cas.15042

Cited by 19 publications

(14 citation statements)

References 64 publications

(134 reference statements)

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“…We also detected other non-redundant immune checkpoints and checkpoint-related gene expression between the two clusters ( Figure 6K ). Several checkpoint molecules, including IFNG, TNFRSF9, CTLA4, CD86, TIM-3, and PD-L2, had significantly increased expression in the low-E-score group, and their effects on T-cell dysfunction and immune escape have been verified in AML ( Hobo et al, 2018 ; Kikushige, 2021 ). However, there was no significant difference, but only a trend, in the expression of PD1 and PDL1, implying that the TME modulation is complicated and understudied.…”

Section: Resultsmentioning

confidence: 91%

eRNAs Identify Immune Microenvironment Patterns and Provide a Novel Prognostic Tool in Acute Myeloid Leukemia

Jiang

Long

Deng

et al. 2022

Front. Mol. Biosci.

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Background: Enhancer RNAs (eRNAs) play an essential role in tumorigenesis as non-coding RNAs transcribed from enhancer regions. However, the landscape of eRNAs in acute myeloid leukemia (AML) and the potential roles of eRNAs in the tumor microenvironment (TME) remain unclear.Method: Gene expression data collected from The Cancer Genome Atlas (TCGA) project were combined with Histone ChIP-seq so as to reveal the comprehensive landscape of eRNAs. Single-sample gene set enrichment analysis algorithm (ssGSEA) and ESTIMATE were employed to enumerate immune cell infiltration and tumor purity.Results: Most prognostic eRNAs were enriched in immune-related pathways. Two distinct immune microenvironment patterns, the immune-active subtype and the immune-resistant subtype, were identified in AML. We further developed an eRNA-derived score (E-score) that could quantify immune microenvironment patterns and predict the response to immune checkpoint inhibitor (ICI) treatment. Finally, we established a prognostic nomogram combining E-score and other clinical features, which showed great discriminative power in both the training set [Harrell’s concordance index (C index): 0.714 (0.651–0.777), p < 0.0001] and validation set [C index: 0.684 (0.614–0.755), p < 0.0001]. Calibration of the nomogram was also validated independently.Conclusion: In this study, we systematically understood the roles of eRNAs in regulating TME diversity and complexity. Moreover, our E-score model provided the first predictive model for ICI treatment in AML.

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Section: Resultsmentioning

confidence: 91%

eRNAs Identify Immune Microenvironment Patterns and Provide a Novel Prognostic Tool in Acute Myeloid Leukemia

Jiang

Long

Deng

et al. 2022

Front. Mol. Biosci.

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“…TIM-3 seems to play a significant role in a compensatory inhibitory mechanism which develops upon treatment with anti-PD-1 and PD-L1 antibodies in breast cancer [ 189 , 190 ]. In leukemia, TIM-3 is an essential receptor for the self-renewal of leukemic stem cells and a great target for anti-leukemia therapy [ 191 ]. Clearly, anti-TIM-3 antibodies hold great promise in oncology.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

Bailly

Thuru

Quesnel

2021

Cancers

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The disaccharide lactose is an excipient commonly used in pharmaceutical products. The two anomers, α- and β-lactose (α-L/β-L), differ by the orientation of the C-1 hydroxyl group on the glucose unit. In aqueous solution, a mutarotation process leads to an equilibrium of about 40% α-L and 60% β-L at room temperature. Beyond a pharmaceutical excipient in solid products, α-L has immuno-modulatory effects and functions as a major regulator of TIM-3/Gal-9 immune checkpoint, through direct binding to the β-galactoside-binding lectin galectin-9. The blockade of the co-inhibitory checkpoint TIM-3 expressed on T cells with anti-TIM-3 antibodies represents a promising approach to combat different onco-hematological diseases, in particular myelodysplastic syndromes and acute myeloid leukemia. In parallel, the discovery and development of anti-TIM-3 small molecule ligands is emerging, including peptides, RNA aptamers and a few specifically designed heterocyclic molecules. An alternative option consists of targeting the different ligands of TIM-3, notably Gal-9 recognized by α-lactose. Modulation of the TIM-3/Gal-9 checkpoint can be achieved with both α- and β-lactose. Moreover, lactose is a quasi-pan-galectin ligand, capable of modulating the functions of most of the 16 galectin molecules. The present review provides a complete analysis of the pharmaceutical and galectin-related biological functions of (α/β)-lactose. A focus is made on the capacity of lactose and Gal-9 to modulate both the TIM-3/Gal-9 and PD-1/PD-L1 immune checkpoints in oncology. Modulation of the TIM-3/Gal-9 checkpoint is a promising approach for the treatment of cancers and the role of lactose in this context is discussed. The review highlights the immuno-regulatory functions of lactose, and the benefit of the molecule well beyond its use as a pharmaceutical excipient.

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“…A current working model implies a permissive Tim-3 bound to Bat3 recruiting Lck and costimulating T cells in opposition to a Tim-3 phosphorylated on tyrosines 256 and 263 by ITK switching from Bat3 to Fyn. In this model, Fyn promotes anergy through the glycosphingolipid-enriched microdomains 1 protein (PAG-1) and the inhibitory C-terminal Src kinase (CSK) [ 79 ].…”

Section: Negative Regulators Of Lymphocyte Function Outside the Cd28 ...mentioning

confidence: 99%

Immune Checkpoint Receptors Signaling in T Cells

Baldanzi

2022

IJMS

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The characterization of the receptors negatively modulating lymphocyte function is rapidly advancing, driven by success in tumor immunotherapy. As a result, the number of immune checkpoint receptors characterized from a functional perspective and targeted by innovative drugs continues to expand. This review focuses on the less explored area of the signaling mechanisms of these receptors, of those expressed in T cells. Studies conducted mainly on PD-1, CTLA-4, and BTLA have evidenced that the extracellular parts of some of the receptors act as decoy receptors for activating ligands, but in all instances, the tyrosine phosphorylation of their cytoplasmatic tail drives a crucial inhibitory signal. This negative signal is mediated by a few key signal transducers, such as tyrosine phosphatase, inositol phosphatase, and diacylglycerol kinase, which allows them to counteract TCR-mediated activation. The characterization of these signaling pathways is of great interest in the development of therapies for counteracting tumor-infiltrating lymphocyte exhaustion/anergy independently from the receptors involved.

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TIM‐3 in normal and malignant hematopoiesis: Structure, function, and signaling pathways

Cited by 19 publications

References 64 publications

eRNAs Identify Immune Microenvironment Patterns and Provide a Novel Prognostic Tool in Acute Myeloid Leukemia

eRNAs Identify Immune Microenvironment Patterns and Provide a Novel Prognostic Tool in Acute Myeloid Leukemia

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

Immune Checkpoint Receptors Signaling in T Cells

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