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

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.

PIWIL1 governs the crosstalk of cancer cell metabolism and immunosuppressive microenvironment in hepatocellular carcinoma

Altered energy metabolism of cancer cells shapes the immune cell response in the tumor microenvironment that faclitates tumorprogression.Herein,we reported the novel of tumor cell-expressed Piwi Like RNA-Mediated Gene Silencing 1(PWL1)in mediatingthe crosstlk of fatty acid metabolism and immune response of human hepatocellular carcinoma(HCC).PlWIL1 expression in HCCwas increased compared to normal hepatic tissues and was positively correlated with the proliferation rate of HCC cell ines.PIWL1overexpression accelerated in vitro proliferation and in vivo growth of HCC tumors,while PIWL1 knockdown showed opositeeffects.PIWL1 increased oxygen consumption and energy production via fatty acid metabolism without altering aerobic glycolysis.lnhibition of fatty acid metablism abolished PWIL1-induced HCC prolferation and growth.RNA-seq analysis revealed that immunesystem regulation might be involved,which was echoed by the experimental observation that PIWL1-overexpressing HCC cellsattracted myeloid-derived suppressor cells(MDSCs)into the tumor microenvironment.MDSCs depletion reduced the prolferationand growth of PlWIL1-overexpressing HCC tumors.Complement C3,whose secretion was induced by PIWL1 in HCC cells,mediatesthe interaction of HCC cells with MDSCs by activated p38 MAPK signaling in MDSCs,which in turn initiated expression of immunosuppressive cytokine L10.Neutralizing lL10 secretion reduced the immunosuppressive activity of MDSCs in the microenvironment of PIWL1-overexpressing HCC.Taken together,our study unraveled the critical role of PIWL1 in initiating theinteraction of cancer cell metabolism and immune cell response in HCC.Tumor cell-expressed PlIWL1 may be a potential target forthe devellopment of novel HCC treatment.