Pancreatic melatonin enhances anti-tumor immunity in pancreatic adenocarcinoma through regulating tumor-associated neutrophils infiltration and NETosis

Tan, Hor‐Yue; Lu, Yuanjun; Zhang, Cheng; Cheng, Chien-Shan; Wu, Junyu; Wang, Ning; Feng, Yibin

doi:10.1016/j.apsb.2023.01.020

Cited by 16 publications

(8 citation statements)

References 65 publications

(72 reference statements)

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“…Recent studies have widely reported this contradictory standpoint that ROS had both anti-tumor and pro-tumor effects 12 , 24 . Chan et al confirmed that NETosis was ROS-dependent in the pancreatic adenocarcinoma mouse model 42 . We observed the higher ROS and lower activity of autophagy in the NET negative neutrophils (Fig.…”

Section: Discussionmentioning

confidence: 92%

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

Fu,

Tao,

et al. 2024

npj Precis. Onc.

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Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm characterized by a poor prognosis and limited therapeutic strategy. The PDAC tumor microenvironment presents a complex heterogeneity, where neutrophils emerge as the predominant constituents of the innate immune cell population. Leveraging the power of single-cell RNA-seq, spatial RNA-seq, and multi-omics approaches, we included both published datasets and our in-house patient cohorts, elucidating the inherent heterogeneity in the formation of neutrophil extracellular traps (NETs) and revealed the correlation between NETs and immune suppression. Meanwhile, we constructed a multi-omics prognostic model that suggested the patients exhibiting downregulated expression of NETs may have an unfavorable outcome. We also confirmed TLR2 as a potent prognosis factor and patients with low TLR2 expression had more effective T cells and an overall survival extension for 6 months. Targeting TLR2 might be a promising strategy to reverse immunosuppression and control tumor progression for an improved prognosis.

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Section: Discussionmentioning

confidence: 92%

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

Fu,

Tao,

et al. 2024

npj Precis. Onc.

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“…Subsequently, we conducted immunofluorescence staining of cfDNA, MPO, and CitH3 to validate the notable inhibition of NETosis upon treatment with CAC extract. Previous studies have documented significant neutrophil infiltration in the synovial membranes of arthritis-afflicted mice, with neutrophil depletion effectively impeding the progression of RA [ 41 – 43 ]. Consequently, targeting dysregulated neutrophils emerges as a crucial therapeutic approach for managing RA.…”

Section: Discussionmentioning

confidence: 99%

Cayratia albifolia C.L.Li exerts anti-rheumatoid arthritis effect by inhibiting macrophage activation and neutrophil extracellular traps (NETs)

Wang,

Zhang,

Zhang

et al. 2024

Chin Med

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Background Cayratia albifolia C.L.Li (CAC), commonly known as “Jiao-Mei-Gu” in China, has been extensively utilized by the Dong minority for several millennia to effectively alleviate symptoms associated with autoimmune diseases. CAC extract is believed to possess significant anti-inflammatory properties within the context of Dong medicine. However, an in-depth understanding of the specific pharmaceutical effects and underlying mechanisms through which CAC extract acts against rheumatoid arthritis (RA) has yet to be established. Methods Twenty-four Sprague–Dawley rats were divided into four groups, with six rats in each group. To induce the collagen-induced arthritis (CIA) model, the rats underwent a process of double immunization with collagen and adjuvant. CAC extract (100 mg/kg) was orally administered to rats. The anti-RA effects were evaluated in CIA rats by arthritis score, hind paw volume and histopathology analysis. Pull-down assay was conducted to identify the potential targets of CAC extract from RAW264.7 macrophage lysates. Moreover, mechanism studies of CAC extract were performed by immunofluorescence assays, real-time PCR and Western blot. Results CAC extract was found to obviously down-regulate hind paw volume of CIA rats, with diminished inflammation response and damage. 177 targets were identified from CAC extract by MS-based pull-down assay. Bioinformatics analysis found that these targets were mainly enriched in macrophage activation and neutrophils extracellular traps (NETs). Additionally, we reported that CAC extract owned significant anti-inflammatory activity by regulating PI3K-Akt-mTOR signal pathway, and inhibited NETosis in response to PMA. Conclusions We clarified that CAC extract significantly attenuated RA by inactivating macrophage and reducing NETosis via a multi-targets regulation. Graphical Abstract

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“…Recently, a study found that melatonin promoted the infiltration of N1 subtype neutrophils by CXCL2, which killed pancreatic cancer cells by NET-derived ROS, indicating the antitumor effect of NETs [75]. It is unclear whether NETs from different subtypes of neutrophils have different effects on tumors, but it has been proved that N1 neutrophils exhibit higher levels of ROS and oxidative burst compared with N2 neutrophils [76].…”

Section: Discussionmentioning

confidence: 99%

Targeting Neutrophil Extracellular Traps: A Novel Antitumor Strategy

Zuo,

Yang,

et al. 2023

Journal of Immunology Research

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The clinical efficacy of surgery, radiotherapy, and chemotherapy for cancer is usually limited by the deterioration of tumor microenvironment (TME). Neutrophil extracellular traps (NETs) are decondensed chromatin extruded by neutrophils and are widely distributed among various cancers, such as pancreatic cancer, breast cancer, and hepatocellular carcinoma. In the TME, NETs interact with stromal components, immune cells and cancer cells, which allows for the reshaping of the matrix and the extracellular environment that favors the initiation, progression, and metastasis of cancer. In addition, NETs impair the proliferation and activation of T cells and NK cells, thus producing a suppressive TME that restricts the effect of immunotherapy. A better understanding of the function of NETs in the TME will provide new opportunities for the prevention of cancer metastasis and the discovery of novel therapy strategies.

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Pancreatic melatonin enhances anti-tumor immunity in pancreatic adenocarcinoma through regulating tumor-associated neutrophils infiltration and NETosis

Cited by 16 publications

References 65 publications

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

Cayratia albifolia C.L.Li exerts anti-rheumatoid arthritis effect by inhibiting macrophage activation and neutrophil extracellular traps (NETs)

Targeting Neutrophil Extracellular Traps: A Novel Antitumor Strategy

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