Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma

Xu, Lixiang; Huang, Ying; Tan, Linlin; Yu, Wei; Chen, Dongdong; Lu, Changchang; He, Jianying; Wu, Guoqing; Liu, Xiaoguang; Zhang, Yongkui

doi:10.1016/j.intimp.2015.09.017

Cited by 170 publications

(133 citation statements)

References 34 publications

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“…Similarly, increased Tim‐3 expression in peripheral NK cells (CD3 − CD56 + and CD3 + CD56 dim ) predicts a poor prognosis and Tim‐3 blockade improves NK cell‐mediated cytotoxicity in human lung adenocarcinoma. Blockade of Tim‐3 on NK cells from patients with lung adenocarcinoma results in increased cytotoxicity and IFN‐γ production . Taken together, current studies from different cancers suggest that the elevated expression of Tim‐3 on NK cells, similar to its expression on CD8 + T cells, suppresses their anti‐tumor function and that Tim‐3 serves as a key molecule to drive functional exhaustion in NK cells.…”

Section: Tim‐3 Expression In the Immune System And Its Functional Indmentioning

confidence: 78%

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

Das

Zhu

Kuchroo

2017

Immunological Reviews

649

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 Expression In the Immune System And Its Functional Indmentioning

confidence: 78%

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

Das

Zhu

Kuchroo

2017

Immunological Reviews

649

507

View full text Add to dashboard Cite

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“…In contrast, in advanced melanoma patients, Tim-3 marks functionally exhausted NK cells with impaired IFN-γ secretion and cytotoxicity (da Silva et al 2014). Moreover, in this context Tim-3 expression levels on NK cells correlate with poor prognosis (da Silva et al 2014; Xu et al 2015). Furthermore, Tim-3 blockade reverses the exhausted phenotype and restores NK function (da Silva et al 2014; Xu et al 2015), suggesting that, similar to its role in CD8 + CTLs, Tim-3 not only marks exhausted NK cells but also contributes to their dysfunction in cancer settings.…”

Section: Tim-3mentioning

confidence: 99%

Tim-3, Lag-3, and TIGIT

Joller

Kuchroo

2017

Current Topics in Microbiology and Immunology

118

106

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Co-inhibitory receptors play a key role in regulating T cell responses and maintaining immune homeostasis. Their inhibitory function prevents autoimmune responses but also restricts the ability of T cells to mount effective immune responses against tumors or persistent pathogens. T cells express a module of co-inhibitory receptors, which display great diversity in expression, structure, and function. Here, we focus on the co-inhibitory receptors Tim-3, Lag-3, and TIGIT and how they regulate T cell function, maintenance of self-tolerance, their role in regulating ongoing T cell responses at peripheral tissues, and their synergistic effects in regulating autoimmunity and antitumor responses.

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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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Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma

Cited by 170 publications

References 34 publications

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

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

Tim-3, Lag-3, and TIGIT

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

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