Tim-3 Hampers Tumor Surveillance of Liver-Resident and Conventional NK Cells by Disrupting PI3K Signaling

Tan, Siyu; Xu, Yong; Wang, Zehua; Wang, Tixiao; Du, Xianhong; Song, Xiaojia; Guo, Xiaowei; Peng, Jiali; Zhang, Jie; Liang, Yan; Liang, Jinghui; Peng, Jun; Gao, Chengjiang; Wu, Zhuanchang; Li, Chunyang; N, Li; Gao, Lifen; Liang, Xiaohong; Hong, Chun Pyo

doi:10.1158/0008-5472.can-19-2332

Cited by 98 publications

(80 citation statements)

References 41 publications

(48 reference statements)

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“…TIM-3 blockade exacerbated the disease phenotype in experimental allergic encephalomyelitis animal models, indicating TIM-3 as a negative regulatory molecule ( 3 ). TIM-3 is widely expressed on immune cells, such as T cells, NK cells ( 46 ), DCs and monocytes/macrophages ( 47 , 48 ). The results of Yan et al strongly suggested that increased TIM-3 expression in monocytes/tumor-associated macrophages was positively correlated with higher tumor grades and the poor survival in patients with HCC ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Values of TIM-3 Expression in Patients With Solid Tumors: A Meta-Analysis and Database Evaluation

Qin

Dong

et al. 2020

Front. Oncol.

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Background: T cell immunoglobulin and mucin-domain containing molecule-3 (TIM-3), a novel emerging immune checkpoint molecule, was reported to express both on various kinds of immune cells and tumor cells. Many previous studies have investigated the prognostic significance of TIM-3 in cancer. However, the sample number from single study was limited and results remained controversial. Methods: We searched PubMed, Web of Science, and Embase databases for publications concerning TIM-3 expression in solid cancers up to March 2020. The correlations between TIM-3 and survival as well as clinical-pathological features were analyzed. Pooled hazard ratios (HRs), odds ratios (ORs), and 95% confidence interval (CI) were estimated by either fixed or random effects models. Results: A total of 3,072 patients were included in our meta-analysis. The result suggested that TIM-3 protein overexpression was relevant to poor overall survival (HR = 1.73, 95% CI = 1.39-2.15, P < 0.001). Moreover, TIM-3 was shown to be connected with lymph node metastasis (N+ vs. NOR OR = 1.59, 95% CI = 1.10-2.29, P = 0.013), tumor grade (G2-3 vs. G1, OR = 1.68, 95% CI = 1.21-2.34, P = 0.002), as well as PD-1 expression (PD-1 high vs. PD-1 low , OR = 3.26, 95% CI = 2.20-4.82, P < 0.001). In database test, significant correlations between high TIM-3 mRNA expression and poor overall survival for patients with non-small cell lung cancer and gastric cancer were observed (

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Section: Discussionmentioning

confidence: 99%

Prognostic Values of TIM-3 Expression in Patients With Solid Tumors: A Meta-Analysis and Database Evaluation

Qin

Dong

et al. 2020

Front. Oncol.

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“…This inconsistency could be due to the complexity and heterogenicity of tissue NK cells. Hepatic NK cells have been shown to have distinct functions in antiviral and antitumor immunity 64,65 . Further studies are needed to clarify the possible involvement of NK cells and other immune cells in IL‐37‐mediated tumoral angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

The indirect antiangiogenic effect of IL-37 in the tumor microenvironment

Zhu

Teo

et al. 2020

Journal of Leukocyte Biology

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IL-37, a newly identified IL-1 family cytokine, has been shown to play an important role in inflammatory diseases, autoimmune diseases, and carcinogenesis. IL-37 has been suggested to suppress tumoral angiogenesis, whereas some publications showed that IL-37 promoted angiogenesis through TGF-signaling in both physiologic and pathologic conditions. Therefore, the function of IL-37 in tumoral angiogenesis is not clear and the underlying mechanism is not known.In this current study, we investigated the direct role of IL-37 on endothelial cells, as well as its indirect effect on angiogenesis through functioning on tumor cells both in vitro and in vivo. We found that IL-37 treatment directly promoted HUVEC migration and tubule formation, indicating IL-37 as a proangiogenic factor. Surprisingly, the supernatants from IL-37 overexpressing tumor cell line promoted HUVEC apoptosis and inhibited its migration and tubule formation. Furthermore, we demonstrated that IL-37 suppressed tumor angiogenesis in a murine orthotopic hepatocellular carcinoma model, suggesting its dominant antiangiogenesis role in vivo. Moreover, microarray and qPCR analysis demonstrated that IL-37 reduced the expressions of proangiogenic factors and increased the expressions of antiangiogenic factors by tumor cells. Matrix metalloproteinase (MMP)2 expression was significantly decreased by IL-37 in both cell lines and murine tumor models. MMP9 and vascular endothelial growth factor expressions were also reduced in murine tumors overexpressing IL-37, as well as in cell lines overexpressing IL-37 under hypoxic conditions. In conclusion, although IL-37 could exert direct proangiogenic effects on endothelial cells, it plays an antiangiogenic role via modulating proangiogenic and antiangiogenic factor expressions by tumor cells in the tumor microenvironment.

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“…Mechanistically, the binding of the endogenous ligand PtdSer with TIM-3 induced the dysregulation of NK cells through interrupting the PI3K/mTORC1/p-S6 signaling pathway. Importantly, TIM-3 knockdown or antibody blockade reduced tumor growth and prolonged the overall survival of orthotopical liver tumor-bearing mice in an NK cell-dependent manner (79). TNF-α was reported to induce NK cell expression of TIM-3 and NK cell dysfunction via the NF-κB pathway.…”

Section: Tim-3mentioning

confidence: 99%

“…TIM-3 is highly expressed on peripheral NK cells from patients with various types of solid tumors, such as lung cancer, gastric cancer, and advanced melanoma, and correlates with NK cell dysfunction and exhaustion ( 76 – 78 ). Tumor-infiltrating NK cells in particular show upregulated TIM-3 expression, which can predict poor prognosis in patients with liver cancer, NSCLC, endometrial cancer, and other types of tumors ( 79 – 81 ). Both conventional NK cells and liver-resident NK cells from patients with liver cancer express high levels of TIM-3, accompanied by decreased capacity of cytokine production and cytotoxicity ( 79 ).…”

Section: The Key Nk Cell Checkpoint Receptors or Molecules That Contrmentioning

confidence: 99%

“…Tumor-infiltrating NK cells in particular show upregulated TIM-3 expression, which can predict poor prognosis in patients with liver cancer, NSCLC, endometrial cancer, and other types of tumors ( 79 – 81 ). Both conventional NK cells and liver-resident NK cells from patients with liver cancer express high levels of TIM-3, accompanied by decreased capacity of cytokine production and cytotoxicity ( 79 ). The percentages of tumor-infiltrating TIM-3 + NK cells correlated negatively with the survival of patients with HCC.…”

Section: The Key Nk Cell Checkpoint Receptors or Molecules That Contrmentioning

confidence: 99%

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Targeting NK Cell Checkpoint Receptors or Molecules for Cancer Immunotherapy

Zhang¹,

Liu²

2020

Front. Immunol.

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Checkpoint blockade therapy, for example using antibodies against CTLA-4 and PD-1/PD-L1, relieves T cells from the suppression by inhibitory checkpoints in the tumor microenvironment; thereby achieving good outcomes in the treatment of different cancer types. Like T cells, natural killer (NK) cell inhibitory receptors function as checkpoints for NK cell activation. Upon interaction with their cognate ligands on infected cells, tumor cells, dendritic cells and regulatory T cells, signals from these receptors severely affect NK cells' activation and effector functions, resulting in NK cell exhaustion. Checkpoint inhibition with antagonistic antibodies (Abs) can rescue NK cell exhaustion and arouse their robust anti-tumor capacity. Most notably, the response to anti-PD-1 therapy can be enhanced by the increased frequency and activation of NK cells, thereby increasing the overall survival of patients with multiple types of cancer. In addition, rescue of NK cell activity could enhance adaptive T cells' anti-tumor activity. Some antagonistic Abs (e.g., anti-TIGIT and anti-NKG2A monoclonal Abs) have extraordinary potential in cancer therapy, as evidenced by their induction of potent anti-tumor immunity through recovering both NK and T cell function. In this review, we summarize the dysfunction of NK cells in the tumor microenvironment and the key NK cell checkpoint receptors or molecules that control NK cell function. We particularly focus on recent advances in the most promising strategies through blockade of NK cell checkpoints or their combination with other approaches to more effectively reject tumors.

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Tim-3 Hampers Tumor Surveillance of Liver-Resident and Conventional NK Cells by Disrupting PI3K Signaling

Cited by 98 publications

References 41 publications

Prognostic Values of TIM-3 Expression in Patients With Solid Tumors: A Meta-Analysis and Database Evaluation

Prognostic Values of TIM-3 Expression in Patients With Solid Tumors: A Meta-Analysis and Database Evaluation

The indirect antiangiogenic effect of IL-37 in the tumor microenvironment

Targeting NK Cell Checkpoint Receptors or Molecules for Cancer Immunotherapy

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