Spatial distribution and functional analysis define the action pathway of Tim-3/Tim-3 ligands in tumor development

Wang, Tixiao; Zhang, Jie; Li, Na; Li, Mengzhen; Ma, Shuaiya; Tan, Siyu; Guo, Xiaowei; Wang, Zehua; Wu, Zhuanchang; Gao, Lifen; Ma, Chao; Liang, Xiaohong

doi:10.1016/j.ymthe.2021.11.015

Cited by 8 publications

(4 citation statements)

References 49 publications

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“…In recent years, the study of the tumor immune microenvironment has taken a leading role in field of cancer research ( Wang et al, 2022 ). The differential expression of immune genes is an important molecular mechanism leading to changes in the tumor immune microenvironment ( Anderson, 2020 ; Peña-Romero and Orenes-Piñero, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

A novel immune-related radioresistant lncRNAs signature based model for risk stratification and prognosis prediction in esophageal squamous cell carcinoma

Zheng

Chen

Huang³

et al. 2022

Front. Genet.

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Background and purpose: Radioresistance remains a major reason of radiotherapeutic failure in esophageal squamous cell carcinoma (ESCC). Our study is to screen the immune-related long non-coding RNA (ir-lncRNAs) of radiation-resistant ESCC (rr-ESCC) via Gene Expression Omnibus (GEO) database and to construct a prognostic risk model.Methods: Microarray data (GSE45670) related to radioresistance of ESCC was downloaded from GEO. Based on pathologic responses after chemoradiotherapy, patients were divided into a non-responder (17 samples) and responder group (11 samples), and the difference in expression profiles of ir-lncRNAs were compared therein. Ir-lncRNA pairs were constructed for the differentially expressed lncRNAs as prognostic variables, and the microarray dataset (GSE53625) was downloaded from GEO to verify the effect of ir-lncRNA pairs on the long-term survival of ESCC. After modelling, patients are divided into high- and low-risk groups according to prognostic risk scores, and the outcomes were compared within groups based on the COX proportional hazards model. The different expression of ir-lncRNAs were validated using ECA 109 and ECA 109R cell lines via RT-qPCR.Results: 26 ir-lncRNA genes were screened in the GSE45670 dataset with differential expression, and 180 ir-lncRNA pairs were constructed. After matching with ir-lncRNA pairs constructed by GSE53625, six ir-lncRNA pairs had a significant impact on the prognosis of ESCC from univariate analysis model, of which three ir-lncRNA pairs were significantly associated with prognosis in multivariate COX analysis. These three lncRNA pairs were used as prognostic indicators to construct a prognostic risk model, and the predicted risk scores were calculated. With a median value of 2.371, the patients were divided into two groups. The overall survival (OS) in the high-risk group was significantly worse than that in the low-risk group (p < 0.001). The 1-, 2-, and 3-year prediction performance of this risk-model was 0.666, 0.702, and 0.686, respectively. In the validation setting, three ir-lncRNAs were significantly up-regulated, while two ir-lncRNAs were obviouly down-regulated in the responder group.Conclusion: Ir-lncRNAs may be involved in the biological regulation of radioresistance in patients with ESCC; and the prognostic risk-model, established by three ir-lncRNAs pairs has important clinical value in predicting the prognosis of patients with rr-ESCC.

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Section: Discussionmentioning

confidence: 99%

A novel immune-related radioresistant lncRNAs signature based model for risk stratification and prognosis prediction in esophageal squamous cell carcinoma

Zheng

Chen

Huang³

et al. 2022

Front. Genet.

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“…Encouraging response rates have been reported with anti-TIM-3 antibodies for MDS and AML treatments, but the effect of TIM-3 blockade has been much less promising in patients with chronic lymphocytic leukemia [ 16 ]. TIM-3 is no cure-all for every cancer, and we need to comprehend further the biology of the target [ 197 ]. The use of lactose as a modulator of TIM-3/Gal-9 is interesting but it raises questions because it is a very common molecule in food and a common pharmaceutical excipient.…”

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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“…Details of the panels and the relative antibodies are provided in Table 2 . Each stained slide was visualized and quantified using a TissueFAXS Spectra System and StrataQuest analysis (TissueGnostics), according to previously described methods ( 25 ). The immune checkpoint molecule expression analysis is performed using the contextual tissue cytometry image analysis.…”

Section: Methodsmentioning

confidence: 99%

Immune checkpoint ligands expressed on mature high endothelial venules predict poor prognosis of NSCLC: have a relationship with CD8+ T lymphocytes infiltration

Luo,

Shi,

Liu

et al. 2024

Front. Immunol.

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BackgroundAn insufficient number of intratumoral CD8+ T lymphocytes is a major barrier to antitumor immunity and immunotherapy. High endothelial venules (HEVs) are the major sites through which lymphocytes enter tumors; however, the molecular mechanism through which HEVs mediate CD8+ T lymphocyte infiltration remains poorly understood.MethodsForty-two patients with stage IIIA lung adenocarcinoma, who underwent surgery, were recruited. Multiplex immunohistochemical staining was conducted on tumor tissues to detect the immune checkpoint ligands (ICLs) expressed in the HEVs, blood vessels, and lymphatics. A new ICL score model was constructed to evaluate ligand expression. The relationship between ICL score, tumor-infiltrating CD8+ T cell frequency, and survival of patients was investigated.ResultsMature HEVs, but not blood vessels or lymphatics, mediated CD8+ T cell infiltration. However, the ICLs expressed on mature HEVs could negatively regulate CD8+ T cell entry into tertiary lymphoid structures (TLSs). In addition, according to the results obtained using our ICLtotal score model, the expression of ICLs on HEVs was observed to be a predictor of both CD8+ T cell infiltration and survival, in which a high ICLtotal score > 1 represent a weak CD8+ T cell infiltration and a high ICLtotal score > 2 predicts poor survival.ConclusionUsing the ICL score model, we discovered that ICLs expressed on HEVs are indicative of CD8+ T cell subset infiltration in TLSs, as well as of patient survival with lung cancer.

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Spatial distribution and functional analysis define the action pathway of Tim-3/Tim-3 ligands in tumor development

Cited by 8 publications

References 49 publications

A novel immune-related radioresistant lncRNAs signature based model for risk stratification and prognosis prediction in esophageal squamous cell carcinoma

A novel immune-related radioresistant lncRNAs signature based model for risk stratification and prognosis prediction in esophageal squamous cell carcinoma

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

Immune checkpoint ligands expressed on mature high endothelial venules predict poor prognosis of NSCLC: have a relationship with CD8+ T lymphocytes infiltration

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