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

Yau Tuen Chan, Hor Yue Tan, Yuanjun Lu, Cheng Zhang, Chien Shan Cheng, Junyu Wu, Ning Wang*, Yibin Feng*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

6 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1554-1567
Number of pages14
JournalActa Pharmaceutica Sinica B
Volume13
Issue number4
DOIs
Publication statusPublished - Apr 2023

Scopus Subject Areas

  • Pharmacology, Toxicology and Pharmaceutics(all)

User-Defined Keywords

  • Anti-tumor immunity
  • CXCL2
  • Melatonin
  • NETosis
  • Neutrophil extracellular traps
  • Pancreatic adenocarcinoma
  • Tumor microenvironment
  • Tumor-associated neutrophils

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