OxidativestresscontrolsregulatoryTcellapoptosisandsuppressoractivityandPD-L1-blockaderesistanceintumorTomaszMaj1,9,WeiWang1,2,9,JoelCrespo1,3,HongjuanZhang1,WeiminWang1,4,ShuangWei1,LiliZhao5,LindaVatan1,IreneShao1,WojciechSzeliga1,CostasLyssiotis6,7,JRebeccaLiu4,IlonaKryczek1,andWeipingZou1,3,7,81DepartmentofSurgery,UniversityofMichiganSchoolofMedicine,AnnArbor,Michigan,USA2DepartmentofImmunologyandKeyLaboratoryofMedicalImmunologyoftheMinistryofPublicHealth,SchoolofBasicMedicalSciences,PekingUniversityHealthScienceCenter,Beijing,China3RackhamGraduateSchool,UniversityofMichigan,AnnArbor,Michigan,USA4DepartmentofObstetricsandGynecology,UniversityofMichiganSchoolofMedicine,AnnArbor,Michigan,USA5DepartmentofBiostatistics,UniversityofMichiganSchoolofMedicine,AnnArbor,Michigan,USA6DepartmentofMolecularandIntegrativePhysiology,UniversityofMichiganSchoolofMedicine,AnnArbor,Michigan,USA7TheUniversityofMichiganComprehensiveCancerCenter,UniversityofMichigan,AnnArbor,Michigan,USA8DepartmentofPathology,UniversityofMichiganSchoolofMedicine,AnnArbor,Michigan,USAAbstractLiveregulatoryTcells(Tregcells)suppressantitumorimmunity,buthowTregcellsbehaveinthemetabolicallyabnormaltumormicroenvironmentremainsunknown.HereweshowthattumorTregcellsundergoapoptosis,andsuchapoptoticTregcellsabolishspontaneousandPD-L1-blockade-mediatedantitumorTcellimmunity.Biochemicalandfunctionalanalysesshowthatadenosine,butnottypicalsuppressivefactorssuchasPD-L1,CTLA-4,TGF-β,IL-35,andIL-10,contributesReprintsandpermissionsinformationisavailableonlineathttp://www.nature.com/reprints/index.html.CorrespondenceshouldbeaddressedtoW.Z.(wzou@med.umich.edu).9Theseauthorscontributedequallytothiswork.AUTHORCONTRIBUTIONST.M.,WeiWang,I.K.,andW.Z.designedtheexperiments.T.M.,I.K.,andW.Z.wrotethepaper.WeiWang,T.M.,J.C.,S.W.,L.V.,andI.K.performedtheinvivotumorexperiments.L.V.,W.S.,I.K.,andJ.R.L.providedandprocessedclinicalspecimensandperformedimmunohistochemicalandpathologicalanalysis.T.M.,WeiWang,H.Z.,I.S.,andWeiminWangp...
