Smac mimetic enables the anticancer action of BCG‐stimulated neutrophils through TNF‐α but not through TRAIL and FasL

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: caspase;    FADD;    c‐;    IAPs;    XIAP;    neutralizing antibodies;   

DOI  :  10.1189/jlb.1211623

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

BCG,thecurrentgoldstandardimmunotherapyforbladdercancer,exertsitsactivityviarecruitmentofneutrophilstothetumormicroenvironment.ManypatientsdonotrespondtoBCGtherapy,indicatingtheneedtounderstandthemechanismofactionofBCG‐stimulatedneutrophilsandtoidentifywaystoovercomeresistancetoBCGtherapy.UsingisolatedhumanneutrophilsstimulatedwithBCG,wefoundthatTNF‐αisthekeymediatorsecretedbyBCG‐stimulatedneutrophils.RT4v6humanbladdercancercells,whichexpressTNFR1,CD95/Fas,CD95ligand/FasL,DR4,andDR5,wereresistanttoBCG‐stimulatedneutrophilconditionedmediumbuteffectivelykilledbythecombinationofconditionedmediumandSmacmimetic.rhTNF‐αandrhFasL,butnotrhTRAIL,incombinationwithSmacmimetic,generatedsignaturemoleculareventssimilartothoseproducedbyBCG‐stimulatedneutrophilsincombinationwithSmacmimetic.However,experimentsusingneutralizingantibodiestothesedeathligandsshowedthatTNF‐αsecretedfromBCG‐stimulatedneutrophilswasthekeymediatorofanticanceraction.ThesefindingsexplainthemechanismofactionofBCGandidentifiedSmacmimeticsaspotentialcombinationtherapeuticagentsforbladdercancer...

【 授权许可】

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