Dual Anti-OX40IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression 英文参考文献.docVIP

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Dual Anti-OX40IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression 英文参考文献.doc

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Dual Anti-OX40IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression 英文参考文献

DualAnti-OX40/IL-2TherapyAugmentsTumor ImmunotherapyviaIL-2R-MediatedRegulationofOX40 Expression WilliamL.Redmond1*,ToddTriplett1,2,KevinFloyd1,AndrewD.Weinberg1,2 1Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon, United States of America, 2DepartmentofMolecularMicrobiologyandImmunology,OregonHealthScienceUniversity,Portland,Oregon,UnitedStatesofAmerica Abstract TheprovisionofTcellco-stimulationviamembersoftheTNFRsuper-family,includingOX40(CD134)and4-1BB(CD137), providescriticalsignalsthatpromoteTcellsurvivalanddifferentiation.Recentstudieshavedemonstratedthatligationof OX40canaugmentTcell-mediatedanti-tumorimmunityinpre-clinicalmodelsandmoreimportantly,OX40agonistsare under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressedonna?¨veTcellsbutrather,istransientlyup-regulatedfollowingTCRstimulation.AlthoughTCRengagementis necessaryforinducingOX40expression,thedownstreamsignalsthatregulateOX40itselfremainunclear.Inthisstudy,we demonstratethatOX40expressionisregulatedthroughaTCRandcommongammachaincytokine-dependentsignaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combinedtreatmentwithanagonistanti-OX40mAbandIL-2augmentedtumorimmunotherapyagainstmultipletumor types.Dualtherapywasalsoabletorestorethefunctionofanergictumor-reactiveCD8Tcellsinmicewithlong-termwell- established (.5wks) tumors, leading to increased survival of the tumor-bearing hosts. Together, these data reveal the abilityofTCR/commongammachaincytokinesignalingtoregulateOX40expressionanddemonstrateanovelmeansof augmentingcancerimmunotherapybyprovidingdualanti-OX40/commongammachaincytokine-directedtherapy. Citation:RedmondWL,TriplettT,FloydK,WeinbergAD(2012)DualAnti-OX40/IL-2TherapyAugmentsTumorImmunotherapyviaIL-2R-MediatedRegulationof OX40Expression.PLoSONE7(4):e34467.doi:10.137