cGAS-STING激动剂cGAMP可增强自然杀伤细胞的抗胃癌效应

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Abstract： Objective Toexplore themolecular mechanism by which cyclic GMP-AMPsynthase-stimulatorofinterferon genes （cGAS-STING）agonistsenhancecytotoxicityofnaturalkiler（NK）cellsagainstgastriccancercell.MethodsNK-92ellswere culturedinX-VIVO15mediumtoadensityof 1×106/mL andtreatedwith5，1，or 0.2μmol/L cGAMP for 24h beforeco-culture with gastric cancer MGC-803 and MKN-45cells in RPMI 1640 medium.The expression of IFN- γ in co-cultured NK-92cells and tumorcellswasdetectedbyqPCRandELISA.ThetreatedNK-92celswerethenco-culturedwiththetumorcellslabeledwith CelTrackerCM-Diatdiferentratios（1：12：1and4：1）andumorcellviabilityandcytotoicityofNK-9cellsere determinedusingadeadcellstainingkitandflowcytometry-based cytotoxicityassay.ResultsThecGAS-STINGagonist cGAMPdose-dependently enhanced mRNA expresionandsecretionof the pro-inflammatory cytokines （such as IFN- γ and TNF- α ） inNK-92cells，andNK-92 cells treatedwith 5μmol/L cGAMP showed approximately 3-fold increase of IFN- γ and TNF- α levels. GAMP treatment also upregulated the expression of activating receptors （such as NKp36and NKp44）on the cell surface and activated the STING-TBK1-IRF3 signalingpathway inNK-92cels.NK-92celspretreatedwithcGAMP showed increased cytotoxicityagainstMGC-803andMKN-45cels，whichcouldbereversedbytreatment withH-151（a STING inhibitor）.Intumor-bearingnudemice，combinedtreatmentwithcGAMPandNKcelsreducedthemassofenogafts bynearly 40% and significantly slowed tumor growth. Conclusion Activating the cGAS-STING pathway can enhance IFN- γ secretionofNKcelstoimprovetheircytotoxicityagainstgastriccancer cells，suggestingatherapeuticstrategyforgastric cancerusing NK cells combined with STING agonists.

Keywords： cGAS-STING; Gastric cancer cells; NK-92 cells; Tumor Immunotherapy

胃癌是全球范围内严重威胁人类健康的重大疾病，其发病率和死亡率居高不下。（剩余13660字）