《HER2Specific T Lymphocytes Kill both TrastuzumabResistant and TrastuzumabSensitive Breast Cell Lines In Vitro》.pdfVIP

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《HER2Specific T Lymphocytes Kill both TrastuzumabResistant and TrastuzumabSensitive Breast Cell Lines In Vitro》.pdf

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HER2-SpecificTLymphocytesKillbothTrastuzumab-Resistant andTrastuzumab-SensitiveBreastCellLinesInVitro Xiao-linLin1 Xiao-liWang1 BoMa1 JunJia1 YingYan1 Li-junDi1 Yan-huaYuan1 Feng-lingWan1, Yuan-liLu1, XuLiang1, TaoShen2, JunRen1 1KeyLaboratoryofCarcinogenesisandTranslationalResearch(MinistryofEducation),DepartmentofBreastCancer,PekingUniversity CancerHospitalInstitute,Beijing100142,China 2KeyLaboratoryofGeriatrics,BeijingHospitalBeijingInstituteofGeriatrics,MinistryofHealth,Beijing100730,China 10.1007/sl1670-012-0143-6 Objective:Althoughthedevelopmentoftrastuzumabhasimprovedtheoutlookforwomenwithhuman epidermalgrowthfactorreceptor2(HER2)-positivebreastcancer,theresistancetoanti-HER2therapyisagrowing clinicaldilemma.WeaimtodeterminewhetherHER2-specificTcellsgeneratedfromdendriticcells(DCs)modified withHER2genecouldeffectivelykilltheHER2-positivebreastcancercells,especiallythetrastuzumab-resistantcells. Methods:Theperipheralbloodmononuclearcells(PBMCs)fromhealthydonors,whoseHLAhaplotypeswere compatiblewiththetumorcelllines,weretransfectedwithreconstructivehumanadeno-associationvirus (rhAAV/HER2)toobtainthespecifickillingactivitiesofTcells,andwereevaluatedbylactatedehydrogenase(LDH) releasingassay. Results:TrastuzumabproducedasignificantinhibitingeffectonSK-BR-3,theIC50was100ng/ml.MDA-MB-453 wasresistanttotrastuzumabevenataconcentrationof10,000ng/mlinvitro.HER2-specificTlymphocyteskilled effectivelySK-BR-3[(69.86±13.41)％]andMDA-MB-453[(78.36±10.68)％]at40:1(effector:targetratio,E:T),buthad nosignificantcytotoxicityagainstHER2-negativebreastcancercelllinesMDA-MB-231orMCF-7(lessthan10％). Conclusion:ThestudyshowedthatHER2-specificTlymphocytesgeneratedfromDCsmodifiedbyrhAAV/HER2 couldkillHER2-positivebreastcancercelllinesinaHER2-dependentmanner,andresultinsignificantlyhigh inhibitionratesontheintrinsictrastuzumab-resistantcelllineMDA-MB-453andthetastuzumab-sensitivecellline