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

TitlePancreatic melatonin enhances anti-tumor immunity in pancreatic adenocarcinoma through regulating tumor-associated neutrophils infiltration and NETosis
Authors
Chan, YTTan, HYLu, YJZhang, CCheng, CSWu, JYWang, NFeng, YB
Issue Date18-Nov-2022
PublisherElsevier
Citation
Acta Pharmaceutica Sinica B, 2023, v. 13, n. 4, p. 1554-1567 How to Cite?
DOI: http://dx.doi.org/10.1016/j.apsb.2023.01.020
Abstract

Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma (PAAD) patients. Proper regulation could improve survival. Melatonin is an endogenous hormone that delivers multiple bioactivities. Here we showed that pancreatic melatonin level is associated with patients' survival. In PAAD mice models, melatonin supplementation suppressed tumor growth, while blockade of melatonin pathway exacerbated tumor progression. This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils (TANs), and TANs depletion reversed effects of melatonin. Melatonin induced TANs infiltration and activation, therefore induced cell apoptosis of PAAD cells. Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of Cxcl2 from tumor cells. Knockdown of Cxcl2 in tumor cells abolished neutrophil migration and activation. Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype, with increased neutrophil extracellular traps (NETs) causing tumor cell apoptosis through cell-to-cell contact. Proteomics analysis revealed that this reactive oxygen species (ROS)-mediated inhibition was fueled by fatty acid oxidation (FAO) in neutrophils, while FAO inhibitor abolished the anti-tumor effect. Analysis of PAAD patient specimens revealed that CXCL2 expression was associated with neutrophil infiltration. CXCL2, or TANs, combined with NET marker, can better predict patients’ prognosis. Collectively, we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.


Persistent Identifierhttp://hdl.handle.net/10722/328426
ISSN
2211-3835
2023 Impact Factor: 14.7
2023 SCImago Journal Rankings: 3.035

 

DC FieldValueLanguage
dc.contributor.authorChan, YT-
dc.contributor.authorTan, HY-
dc.contributor.authorLu, YJ-
dc.contributor.authorZhang, C-
dc.contributor.authorCheng, CS-
dc.contributor.authorWu, JY-
dc.contributor.authorWang, N-
dc.contributor.authorFeng, YB-
dc.date.accessioned2023-06-28T04:44:49Z-
dc.date.available2023-06-28T04:44:49Z-
dc.date.issued2022-11-18-
dc.identifier.citationActa Pharmaceutica Sinica B, 2023, v. 13, n. 4, p. 1554-1567-
dc.identifier.issn2211-3835-
dc.identifier.urihttp://hdl.handle.net/10722/328426-
dc.description.abstract<p><a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/tumor-microenvironment" title="Learn more about Tumor microenvironment from ScienceDirect's AI-generated Topic Pages">Tumor microenvironment</a> contributes to poor prognosis of <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/pancreas-adenocarcinoma" title="Learn more about pancreatic adenocarcinoma from ScienceDirect's AI-generated Topic Pages">pancreatic adenocarcinoma</a> (PAAD) patients. Proper regulation could improve survival. <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/melatonin" title="Learn more about Melatonin from ScienceDirect's AI-generated Topic Pages">Melatonin</a> is an endogenous hormone that delivers multiple bioactivities. Here we showed that pancreatic melatonin level is associated with patients' survival. In PAAD mice models, melatonin supplementation suppressed tumor growth, while blockade of melatonin pathway exacerbated tumor progression. This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils (TANs), and TANs depletion reversed effects of melatonin. Melatonin induced TANs infiltration and activation, therefore induced cell apoptosis of PAAD cells. Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of <em>Cxcl2</em> from tumor cells. Knockdown of <em>Cxcl2</em> in tumor cells abolished neutrophil migration and activation. Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype, with increased neutrophil extracellular traps (NETs) causing tumor cell apoptosis through cell-to-cell contact. Proteomics analysis revealed that this <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/reactive-oxygen-metabolite" title="Learn more about reactive oxygen species from ScienceDirect's AI-generated Topic Pages">reactive oxygen species</a> (ROS)-mediated inhibition was fueled by fatty acid oxidation (FAO) in neutrophils, while FAO inhibitor abolished the anti-tumor effect. Analysis of PAAD patient specimens revealed that <em>CXCL2</em> expression was associated with neutrophil infiltration. <em>CXCL2</em>, or TANs, combined with NET marker, can better predict patients’ prognosis. Collectively, we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.<br></p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofActa Pharmaceutica Sinica B-
dc.titlePancreatic melatonin enhances anti-tumor immunity in pancreatic adenocarcinoma through regulating tumor-associated neutrophils infiltration and NETosis-
dc.typeArticle-
dc.identifier.doi10.1016/j.apsb.2023.01.020-
dc.identifier.volume13-
dc.identifier.issue4-
dc.identifier.spage1554-
dc.identifier.epage1567-
dc.identifier.issnl2211-3835-

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