Interleukin-37 Mediates the Antitumor Activity in Hepatocellular Carcinoma: Role for CD57+ NK Cells

Zhao, Jing; Pan, Qiu Zhong; Pan, Ke; Weng, De Sheng; Wang, Qi Jing; Li, Jian Jun; Lv, Lin; Wang, Dan Dan; Zheng, Hai Xia; Jiang, Shan; Zhang, Xiao Fei; Xia, Jian Chuan

doi:10.1038/srep05177

Cited by 90 publications

(105 citation statements)

References 33 publications

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“…Previous study also showed that IL‐37 mediated anti‐tumor immune responses through recruiting NK cells to tumor microenvironment in hepatocellular carcinoma 13. However, Ge et al14 found no change in TILs frequencies in tumors over‐expressing IL‐37, suggesting that IL‐37 might not affect the anti‐tumor immune responses in vivo.…”

Section: Discussionmentioning

confidence: 95%

“…IL‐37 has been identified as a natural suppressor of innate inflammatory and immune responses 8, 12. Recent studies have indicated that IL‐37 plays a protective role in tumor progression in mouse fibrosarcoma,9 human lung cancer,14, 42 hepatocellular carcinoma,13 breast cancer,43 cervical cancer,44 and renal cell carcinoma 45. Zhang et al15 found that IL‐37 inhibits colon cancer progression via β‐catenin suppression and that a lack of IL‐37 is associated with poor survival.…”

Section: Discussionmentioning

confidence: 99%

“…Gao et al9 found that the intratumoral injection of IL‐37 inhibited tumor growth and the antitumor activity of IL‐37 was abrogated in mice models. Moreover, the expression of IL‐37 was decreased in tumor tissues of hepatocellular carcinoma patients, and the expression level was negatively correlated with tumor size 13. Also, high levels of IL‐37 were associated with improved overall survival and disease‐free survival 13, 14, 15.…”

Section: Introductionmentioning

confidence: 98%

“…Moreover, the expression of IL‐37 was decreased in tumor tissues of hepatocellular carcinoma patients, and the expression level was negatively correlated with tumor size 13. Also, high levels of IL‐37 were associated with improved overall survival and disease‐free survival 13, 14, 15. Furthermore, the antitumor activity was found by recruiting more NK cells in hepatocellular carcinoma and inhibiting tumor angiogenesis in nonsmall cell lung cancer 13, 14.…”

Section: Introductionmentioning

confidence: 99%

“…Also, high levels of IL‐37 were associated with improved overall survival and disease‐free survival 13, 14, 15. Furthermore, the antitumor activity was found by recruiting more NK cells in hepatocellular carcinoma and inhibiting tumor angiogenesis in nonsmall cell lung cancer 13, 14. Recent study by Zhao found that IL‐37 inhibited colon tumor formation in the mice model and sensitized the cancer cell to chemotherapy drugs 15.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

et al. 2018

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Interleukin (IL)‐37 and neutrophils are considered to be involved in human cancer, but their prognostic significance in colorectal cancer (CRC) has not been elucidated. The aim of this study was to evaluate the prognostic value of IL‐37 expression and neutrophil levels in CRC. We retrospectively analyzed IL‐37 expression, CD66b+ neutrophil levels, and mismatch repair (MMR) status in 337 paraffin‐embedded CRC specimens from the training cohort by immunohistochemistry. Their prognostic values were assessed using Kaplan‐Meier curves and multivariate Cox regression models. Moreover, several risk factors were used to form nomograms to evaluate survival, and the performance of the nomograms was assessed with respect to calibration, discrimination, and clinical usefulness. Further validation was performed in an independent cohort of 245 cases. Low IL‐37 expression and high CD66b+ neutrophil levels were significantly associated with diminished disease‐free survival (DFS) and overall survival (OS), and patients with MMR‐deficient CRC had better clinical outcomes. Furthermore, multivariate Cox analysis identified IL‐37, CD66b+ neutrophils, and MMR status as independent prognostic factors for DFS and OS. Two nomograms integrating the three markers with four clinicopathological risk factors were developed and validated for predicting DFS and OS with good calibration and discrimination (C‐index: training cohort, 0.798 (95% confidence interval:0.764‐0.832) and 0.828 (0.796‐0.860), respectively; validation cohort, 0.739 (0.696‐0.783) and 0.761 (0.715‐0.808), respectively). Decision curve analysis demonstrated that the nomograms were clinically useful. Intratumoral IL‐37, CD66b+ neutrophils, and MMR status were independent prognostic factors for CRC patients. Nomograms incorporating these biomarkers and clinicopathological features could be conveniently used to facilitate the individualized prediction of DFS and OS.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

et al. 2018

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IL‐37: An anti‐inflammatory cytokine with antitumor functions

Liu

2018

Cancer Reports

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Background IL‐37 is a newly identified IL‐1 family cytokine. Unlike other members in IL‐1 family, IL‐37 has been demonstrated to be an anti‐inflammatory cytokine in many inflammatory and autoimmune diseases. IL‐37 is regarded as a dual‐function cytokine as both the extracellular and intracellular IL‐37 are biologically functional. Extracellular IL‐37 can bind to IL‐18Rα and IL‐1R8 to form a triple complex, regulating the downstream STAT3 and PTEN signaling. Intracellular IL‐37 can interact with Smad3, translocate into nucleus, and regulate downstream target gene expressions. Recently, the role of IL‐37 in tumor development has been extensively studied. Recent findings IL‐37 has been found to play an antitumor role in various types of tumors, such as non‐small cell lung cancer, hepatocellular carcinoma, and renal cell carcinoma. Many mechanism studies have been carried out to elaborate the possible effects of IL‐37 on tumor growth, immune responses, and tumor angiogenesis. More importantly, the function of IL‐37 may be dependent on its concentration and receptor expression. It can form dimers at high concentrations to be inactivated, thus inhibiting its anti‐inflammatory function. We focused on the role of IL‐37 in various tumor types and provided the hypothesis regarding the underlying mechanisms. Conclusion IL‐37 may affect tumor development through multiple mechanisms: (1) IL‐37 directly influences tumor cell viability; (2) IL‐37 regulates the immune response to promote the antitumor immunity; and (3) IL‐37 suppresses tumor angiogenesis in the tumor microenvironment. Future studies are warranted to further investigate the mechanisms of these multifaceted functions of IL‐37 in animal models and cancer patients.

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Suppression of innate inflammation and immunity by interleukin‐37

et al. 2016

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IL-37 is unique in the IL-1 family in that unlike other members of the family, IL-37 broadly suppresses innate immunity. IL-37 can be elevated in humans with inflammatory and autoimmune diseases where it likely functions to limit inflammation. Transgenic mice expressing human IL-37 (IL37-tg) exhibit less severe inflammation in models of endotoxin shock, colitis, myocardial infarction, lung and spinal cord injury. IL37-tg mice have reduced antigen-specific responses and dendritic cells (DCs) from these mice exhibit characteristics of tolerogenic DCs. Compared to aging wild-type (WT) mice, aging IL37-tg mice are protected against B-cell leukemogenesis and heart failure. Treatment of WT mice with recombinant human IL-37 has been shown to be protective in several models of inflammation and injury. IL-37 binds to the IL-18 receptor but then recruits the orphan IL-1R8 (formerly TIR8 or Sin order function as an inhibitor. Here we review the discovery of IL-37, its production, release and mechanisms by which IL-37 reduces inflammation and suppresses immune responses. The data reviewed here suggest a therapeutic potential for IL-37.

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Interleukin-37 Mediates the Antitumor Activity in Hepatocellular Carcinoma: Role for CD57+ NK Cells

Cited by 90 publications

References 33 publications

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

IL‐37: An anti‐inflammatory cytokine with antitumor functions

Suppression of innate inflammation and immunity by interleukin‐37

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