NF-κBc-RelIsCrucialfortheRegulatoryTCellImmuneCheckpointinCancerYenkelGrinberg-Bleyer1,HyunjuOh1,AlexisDesrichard2,DevM.Bhatt1,RachelCaron1,TimothyA.Chan2,RolandM.Schmid3,MatthewS.Hayden1,5,UlfKlein1,4,6,andSankarGhosh1,71DepartmentofMicrobiology&Immunology,CollegeofPhysicians&Surgeons,ColumbiaUniversity,NewYork,NY10032,USA2HumanOncologyandPathogenesisProgram,MemorialSloanKetteringCancerCenter,NewYork,NY10065,USA3IIMedizinischeKlinik,KlinikumRechtsderIsar,TechnischeUniversitätMunich,Munich,Germany4HerbertIrvingComprehensiveCancerCenterandDepartmentofPathology&CellBiology,CollegeofPhysicians&Surgeons,ColumbiaUniversity,NewYork,NY10032,USA5SectionofDermatology,DepartmentofSurgery,Dartmouth-HitchcockMedicalCenter,Lebanon,NH03756,USASummaryRegulatoryTcells(Tregs)playapivotalroleintheinhibitionofanti-tumorimmuneresponses.UnderstandingthemechanismsgoverningTreghomeostasismaythereforebeimportantfordevelopmentofeffectivetumorimmunotherapy.WehaverecentlydemonstratedakeyroleforthecanonicalnuclearfactorκB(NF-κB)subunits,p65andc-Rel,inTregidentityandfunction.Inthisreport,weshowthatNF-κBc-RelablationspecificallyimpairsthegenerationandmaintenanceoftheactivatedTreg(aTreg)subset,whichisknowntobeenrichedatsitesoftumors.Usingmousemodels,wedemonstratethatmelanomagrowthisdrasticallyreducedinmicelackingc-Rel,butnotp65,inTregs.Moreover,chemicalinhibitionofc-RelfunctiondelayedmelanomagrowthbyimpairingaTreg-mediatedimmunosuppressionandpotentiatedtheeffectsofanti-PD-1immunotherapy.OurstudiesthereforeestablishinhibitionofNF-κBc-Relasaviabletherapeuticapproachforenhancingcheckpoint-targetingimmunotherapyprotocols.GraphicalabstractCorrespondenceto:SankarGhosh.6Presentaddress:SectionofExperimentalHaematology,LeedsInstituteofCancerandPathology,UniversityofLeeds,LeedsLS29JT,UK7LeadContactAuthorContributions:Y.G.-B.andS.G.conceivedtheexperiments.Y.G.-B.,M.S.H.,andS.G.wrotethepaper.Y.G.-B.,H.O.,andR.C.,performedexperiments.Y.G.-B.,A.D.,D.B.,T.C.,M.S.H.,andS.G.analyzedthedata.U.K.andR.S.pro...
