Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner 英文参考文献.docVIP

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Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner 英文参考文献.doc

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Prime-BoostVaccinationwithSA-4-1BBLCostimulatoryMoleculeandSurvivinEradicatesLungCarcinomainCD8TandNKCellDependentManner英文参考文献

Prime-BoostVaccinationwithSA-4-1BBLCostimulatory MoleculeandSurvivinEradicatesLungCarcinomain CD8 TandNKCellDependentManner + AbhishekK.Srivastava1.,RajeshK.Sharma1.,EsmaS.Yolcu1,VahapUlker2,KathrynMacLeod2, GunesDinc1,HavalShirwan1* 1InstituteforCellularTherapeutics,DepartmentofMicrobiologyandImmunologyandJamesBrownCancerCenter,UniversityofLouisville,Louisville,Kentucky,United StatesofAmerica,2ApoVaxInc.,Louisville,Kentucky,UnitedStatesofAmerica Abstract Subunitvaccinescontaininguniversaltumorassociatedantigens(TAAs)presentanattractivetreatmentmodalityforcancer primarily due to their safety and potential to generate long-term immunological responses that can safeguard against recurrences.However,TAA-basedsubunitvaccinesrequirepotentadjuvantsfortherapeuticefficacy.Usinganovelformof the 4-1BBL costimulatory molecule, SA-4-1BBL, as the adjuvant of choice, we previously demonstrated that a single vaccination with survivin (SVN) as a bona fide self TAA was effective in eradicating weakly immunogenic 3LL tumors in .70%ofC57BL/6mice.Thepresentstudywasdesignedtoi)assessthetherapeuticefficacyofaprime-boostvaccination andii)investigatethemechanisticbasisofvaccineefficacy.Ourdatashowsthataprime-boostvaccinationstrategywas effectiveineradicating3LLlungcarcinomain100%ofmice.Thevaccineefficacywascorrelatedwithincreasedpercentages + + ofCD8 TcellsexpressingIFN-caswellaspotentkillingresponsesofbothCD8 TandNKcellsintheabsenceofdetectable + antibodiestossDNAasasignofautoimmunity.AntibodydepletionofCD8 Tcellsonedaybeforevaccinationcompletely abrogated therapeutic efficacy, whereas depletion of CD4+ T cells had no effect. Importantly, NK cell depletion had a moderate(,50%reduction),butsignificant(p,0.05)effectonvaccineefficacy.Takentogether,theseresultsshedlighton themechanisticbasisoftheSA-4-1BBL/SVNsubunitvaccineformulationinalungcarcinomamodelanddemonstratethe robusttherapeuticefficacyoftheprime-boostimmunizationstrategywithimportantclinicalimplications. Citation: Sriv