Route of Administration of the TLR9 Agonist CpG Critically Determines the Efficacy of Cancer Immunotherapy in Mice 英文参考文献.docVIP

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Route of Administration of the TLR9 Agonist CpG Critically Determines the Efficacy of Cancer Immunotherapy in Mice 英文参考文献.doc

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Route of Administration of the TLR9 Agonist CpG Critically Determines the Efficacy of Cancer Immunotherapy in Mice 英文参考文献

RouteofAdministrationoftheTLR9AgonistCpG CriticallyDeterminestheEfficacyofCancer ImmunotherapyinMice StefanNierkens1,MartijnH.denBrok1,ThijsRoelofsen1,JoriA.L.Wagenaars1,CarlG.Figdor1,TheoJ. Ruers2,GosseJ.Adema1* 1Department ofTumorImmunology,RadboudUniversityNijmegenMedicalCentre,Nijmegen,TheNetherlands,2TheNetherlandsCancerInstitute,Amsterdam,The Netherlands Abstract Background:TheTLR9agonistCpGisincreasinglyappliedinpreclinicalandclinicalstudiesasatherapeuticmodalityto enhancetumorimmunity.TheclinicalapplicationofCpGappears,however,lesssuccessfulthanwouldbepredictedfrom animalstudies.Onereasonmightbethedifferentadministrationroutesappliedinmostmousestudiesandclinicaltrials. We studied whether the efficacy of CpG as an adjuvant in cancer immunotherapy is dependent on the route of CpG administration,inparticularwhenthetumorisdestructedinsitu. Methodology/PrincipalFindings:Insitutumordestructiontechniquesareminimallyinvasivetherapeuticalternativesfor thetreatmentof(nonresectable)solidtumors.Incontrasttosurgicalresection,tumordestructionleadstotheinductionof weak but tumor-specific immunity that can be enhanced by coapplication of CpG. As in situ tumor destruction by cryosurgery creates an instant local release of antigens, we applied this model to study the efficacy of CpG to enhance antitumorimmunitywhenadministratedviadifferentroutes:peritumoral,intravenous,andsubcutaneousbutdistantfrom the tumor. We show that peritumoral administration is superior in the activation of dendritic cells, induction of tumor- specificCTL,andlong-lastingtumorprotection.Althoughtheintravenousandsubcutaneous(atdistantsite)exposuresare commonly used inclinical trials, theyonlyprovided partialprotection or evenfailedto enhanceantitumorresponses as inducedbycryosurgeryalone. Conclusions/Significance: CpG administration greatly enhances the efficacy of in situ tumor destruction techniques, providedthatCpGisadministeredincloseproximityofthereleasedantigens.Hence,thisstudyhelpstoprovidedire