Studiesonthedevelopmentofdeliveryplatformforcancervaccineusingbileacid-lipidnano-assembly

Abstract

Cancervaccinescanelicitaspecificimmuneresponseagainstthetumorandenablelong-termimmunememorybydeliveryoftheantigentoantigen-presentingcells,reducingthetoxicityandpreventingtumorrecurrence.Survivinwhichisoverexpressedinmanycancercellsisinvolvedinapoptosisevasion,tumorprogressionandhasbeenutilizedincancertherapeuticvaccines.Andthedeoxycholicacid(DOCA)hasimmunomodulatoryactivitywhichactivatesneutrophils,enhancesinflammatorymonocytesrecruitment,andmodulatesthephagocyticcapabilityofmonocytes.Inthisstudy,deliveryplatformforcancervaccineusingdeoxycholicacid-lipidnano-assembly(DA-L-DSA)whichco-deliversurvivin(66-74)andsynergisticadjuvants,TLR7/8agonistR848andTGF-βR1inhibitorSD208.Theywereloadedinthelipid-coatednano-assembly.Andtheanti-PD-1monoclonalantibodywascombinedwiththeDA-L-DSAtoimprovetheanti-tumorimmuneresponsebyrestoringTcellresponse.TheDA-L-DSAcaninducematurationofdendriticcellsefficientlywhichisanalyzedbyup-regulationofMHCandco-stimulatorymoleculesandsecretionofproinflammatorycytokines.Thetumorgrowthwasinhibitedinthemiceimmunizedthenano-assemblyvaccineefficientlyinboththerapeuticandprophylacticmelanomamodel.Especially,thecombinationgroupwithDA-L-DSAandanti-PD-1wasshowntoimprovetheanimalsurvivalsignificantly.Furthermore,TheCD8+TcellscouldinfiltratetumortissuesandsecreteIFN-γthatcaninduceapoptosisofthetumorcells.Consequently,theDA-L-DSAandanti-PD-1couldinduceanti-tumoreffectstowardsthemelanoma.|암백신은종양에대한특정면역반응을이끌어낼수있고,항원을항원제시세포에전달한다.이는장기적인면역기억을가능하게해독성을줄이고종양재발을방지할수있는것으로알려져있다.많은암세포에서과다하게발현되는survivin은암세포의증식과세포사멸회피에관여하며암치료백신의종양관련항원으로주목받고있다.디옥시콜산은호중구를활성화하고염증성단핵구의모집을증가시키며단핵구의식세포능력을조절하는면역활성을가지고있다.본연구에서는암의치료및예방을목적으로디옥시콜산-지질나노백신(DA-L-DSA)를이용하여survivin펩타이드및2가지의면역증강제(TLR7/8작용제R848및TGF-βR1억제제SD208)을전달하였다.또한,항PD-1단일클론항체를DA-L-DSA와병용투여하여T세포활성을회복시켜항암면역반응을개선하였다.DA-L-DSA는MHC와공동자극분자의발현을증가시키고,염증성사이토카인을분비시키며수지상세포의성숙을유도하였다.치료및예방흑색종모델에서나노백신을접종한후에종양성장이효과적으로억제되었다.특히,DA-L-DSA와항-PD-1항체를병용투여한그룹은생존율을크게향상시킨것으로나타났다.또한,백신투여후CD8+T세포가종양조직에침투하여IFN-γ를분비함으로써,종양세포의세포사멸을유도하는것이확인되었다.본연구를통해DA-L-DSA와항PD-1이흑색종에대한항종양효과를유도할수있다는것이확인되었다.