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 8 publications

(5 citation statements)

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“…3c ) 45 . At the same time, a recent study also observed the expression of CXCL2 can induce the migration of neutrophils from the peripheral circuit to TME and might account for the liver metastasis after gemcitabine treatment, which might form feedforward recruitment of anti-tumor neutrophils and melatonin was validated to induced the expression of tumor cells rather than macrophages to recruit the neutrophils by upregulated CXCL2 42 , 46 . The following observation provided sufficient evidence for the key immune regulation role and the intrinsic heterogeneity of NETosis.…”

Section: Discussionmentioning

confidence: 91%

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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: 91%

“…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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“…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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“…CXCL2 is involved in cell proliferation, apoptosis, tumor formation and development, and is closely related to the generation and differentiation of megakaryocytes [30] . Studies have shown that CXCL2 is a carcinogenic factor, and patients with high CXCL2 expression are more likely to develop lymph node metastasis [31] . The above study results are consistent with our experimental results.…”

Section: Discussionmentioning

confidence: 99%

Integrating Single-cell RNA-seq to construct a Neutrophil prognostic model for predicting immune responses in cervical carcinoma

Qian,

Xieyidai,

Han

et al. 2023

Preprint

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Objective: The objective of this study is to comprehensively investigate the communication network within the tumor immune microenvironment (Tumor Immune Microenvironment, TIME) of cervical carcinoma (CC). This involves elucidating the intricate relationships among cells to gain a profound understanding of the interactions between immune cells and tumor cells，as well as the assessment of neutrophil differentiation characteristics and the selection of prognostic genes, the primary goal is to establish a risk model with the ability to predict patients' immune responses and prognosis. Additionally, this model seeks to uncover innovative diagnostic and therapeutic targets for cervical carcinoma, thereby furnishing clinicians with dependable strategies for treatment. Methods: Using single-cell RNA sequencing data (scRNA-seq) obtained from CC samples (E-MTAB-11948), this study employed the Seurat(4.3.0) package to integrate data, remove batch effects, and annotate cell types. A cell communication network was constructed using the iTAKL(0.1.0) package for the analysis of intercellular communication. Neutrophil subpopulations were analyzed utilizing the Monocle2(2.26.0) package to discern various cellular states and conduct pathway analysis using KEGG/GO annotations. Results: we successfully distinguished and further categorized 32 cell populations into 9 major cell types, encompassing T cells, B cells, Mast cells, Neutrophils, Epithelial cells, Endothelial cells, Monocytes, Fibroblasts, and Smooth muscle cells. Furthermore, we ascertained that five subgroups of Neutrophils, each representing diverse differentiation states, exhibit close associations with immune regulatory and metabolic pathways.From our analysis of intersecting genes in the TCGA-CESC dataset, we successfully identified four prognostic genes: C5AR1, HSPA5, CXCL2, and OLR1. The stability of our prognostic risk model has been reiterated through internal and external validation, demonstrating its high consistency, differentiation, and clinical applicability. Notably, the CIRBESORT analysis divulged diminished immune cell content within the tumor immune microenvironment of the high-risk group, correlating with an unfavorable prognosis. Low expression of C5AR1 and high expression of HSPA5, CXCL2, and OLR1 were significantly associated with shorter survival and poorer prognosis.Conclusion: This study elucidated the intricate regulatory network governing the immune microenvironment in CC and comprehensively analyzed intercellular interactions.highlighting the significant roles of C5AR1, HSPA5, CXCL2, and OLR1 in predicting patient prognosis and responsiveness to immunotherapy. These findings offer novel insights and potential strategies for identifying fresh treatment targets in CC. Conclusion: This study elucidated the regulatory network of immune microenvironment in CC, and analyzed the interaction between cells. the key roles of C5AR1, HSPA5, CXCL2 and OLR1 in predicting patient prognosis and response to immunotherapy were revealed. This provides new insights and possible strategies for finding new CC treatment targets.

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

Cited by 8 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)

Integrating Single-cell RNA-seq to construct a Neutrophil prognostic model for predicting immune responses in cervical carcinoma

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