The Clinical Significance of Abnormal Tim-3 Expression on NK Cells from Patients with Gastric Cancer

Zhu, Jinlian; Gu, Haidi; Yuan, Yuan; Zhang, Bin; Zhu, Dongming; Zhou, Juxiang; Zhu, Yueyong; Chen, Weichang

doi:10.3109/08820139.2015.1052145

Cited by 65 publications

(50 citation statements)

References 22 publications

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“…The increased Tim‐3 expression on tumor antigen‐specific CD8 + T cells is also correlated with dysfunction of CD8 + T cell and poor prognosis in HBV‐associated hepatocellular carcinoma and prostate cancer patients . Similarly, increased Tim‐3 expression on NK cells from patients with gastric cancer is associated with tumor progression . Collectively, increased expression of Tim‐3 in human tumors, particularly on immune cells, could serve as a potential prognostic biomarker for a variety of tumors.…”

Section: Tim‐3 and Tumormentioning

confidence: 96%

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Tim‐3 and its role in regulating anti‐tumor immunity

Das

Zhu

Kuchroo

2017

Immunological Reviews

624

507

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Summary Immunotherapy is being increasingly recognized as a key therapeutic modality to treat cancer and represents one of the most exciting treatments for the disease. Fighting cancer with immunotherapy has revolutionized treatment for some patients and therapies targeting the immune checkpoint molecules such as CTLA-4 and PD-1 have achieved durable responses in melanoma, renal cancer, Hodgkin’s diseases and lung cancer. However, the success rate of these treatments has been low and a large number of cancers, including colorectal cancer remain largely refractory to CTLA-4 and PD-1 blockade. This has provided impetus to identify other co-inhibitory receptors that could be exploited to enhance response rates of current immunotherapeutic agents and achieve responses to the cancers that are refectory to immunotherapy. Tim-3 is a co-inhibitory receptor that is expressed on IFN-γ-producing T cells, FoxP3+ Treg cells and innate immune cells (macrophages and dendritic cells) where it has been shown to suppress their responses upon interaction with their ligand(s). Tim-3 has gained prominence as a potential candidate for cancer immunotherapy, where it has been shown that in vivo blockade of Tim-3 with other check-point inhibitors enhances anti-tumor immunity and suppresses tumor growth in several preclinical tumor models. This review discusses the recent findings on Tim-3, the role it plays in regulating immune responses in different cell types and the rationale for targeting Tim-3 for effective cancer immunotherapy.

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Section: Tim‐3 and Tumormentioning

confidence: 96%

“…21 Similarly, increased Tim-3 expression on NK cells from patients with gastric cancer is associated with tumor progression. 95 Collectively,increasedexpressionofTim-3inhumantumors,particularlyonimmunecells,couldserveasapotentialprognosticbiomarker foravarietyoftumors.…”

Section: Tim-3asapotentialprognosticbiomarker Forcancersmentioning

confidence: 99%

Tim‐3 and its role in regulating anti‐tumor immunity

Das

Zhu

Kuchroo

2017

Immunological Reviews

624

507

View full text Add to dashboard Cite

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“…While two previous studies have investigated the association between Tim-3 expression on T cells and NK cells, and patient clinicopathological features (47,48). However, the Table VI.…”

Section: Foxp3 Expression ----------------------------------------mentioning

confidence: 99%

Association between Tim‑3 and Gal‑9 expression and gastric cancer prognosis

et al. 2018

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The T‑cell immunoglobulin and mucin domain‑containing protein 3 (Tim‑3)/galectin 9 (Gal‑9) pathway, which serves a pivotal role in immune regulation, is similar to the programmed death (PD)‑1/PD‑ligand 1 pathway. Recent evidence has suggested that Tim‑3 is differentially regulated in a variety of tumors and is a potential therapeutic target. The aim of the present study was to evaluate Tim‑3 and Gal‑9 expression and cluster of differentiation (CD)3+, CD8+ and forkhead box (FOX)p3+ T cell tumor‑infiltration in gastric cancer, as well as their impact on prognosis. Tissue samples from 587 patients with gastric cancer were used to create a tissue microarray (TMA). The immune markers Tim‑3, Gal‑9, CD3, CD8 and FOXp3 were immunostained in the TMA, and correlations with clinicopathological findings and prognosis were analyzed. Several Gene Expression Omnibus gastric cancer databases and the K‑M plotter website were used to analyze the association between the expression of Tim‑3, Gal‑9 and CD8A RNA and patient survival. The results demonstrated that Tim‑3 was mainly expressed in immune cells, with minimal expression in gastric cancer cells. Its ligand, Gal‑9, was significantly overexpressed in tumor cells. Tim‑3 and Gal‑9 expression and Foxp3+ T cell density were negatively associated with the patient overall survival (OS) rate. The density of CD8+ T cells was positively associated with the patient OS rate. Tim‑3 expression and CD8+ T cell density were revealed to be independent prognostic factors for patients with gastric cancer.

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“…The expression of TIM-3, whose cognate ligand is galectin-9, is upregulated in peripheral NK cells from advanced gastric cancer patients 109 and from lung adenocarcinoma patients, 110 suggesting the value of TIM-3 as a predictive or prognostic biomarker. It is also expressed in the tumor-infiltrated NK cells in 75% of patients with gastrointestinal stromal tumor.…”

Section: Immune Checkpoint Inhibitors For Nk Cell Activationmentioning

confidence: 99%

Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy

Kwon

Kim

2017

Exp Mol Med

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Natural killer (NK) cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity. These effector functions are governed by signals transmitted through multiple receptor–ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism. The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors. These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category. Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer.

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The Clinical Significance of Abnormal Tim-3 Expression on NK Cells from Patients with Gastric Cancer

Abstract: Our data indicate that Tim-3 expression on NK cells is regulated by T-bet, and that Tim-3 levels correlate with advanced stages of gastric cancer.

Cited by 65 publications

References 22 publications

Tim‐3 and its role in regulating anti‐tumor immunity

Tim‐3 and its role in regulating anti‐tumor immunity

Association between Tim‑3 and Gal‑9 expression and gastric cancer prognosis

Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy

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