CANCERIMMUNOTHERAPYGutmicrobiomeinfluencesefficacyofPD-1–basedimmunotherapyagainstepithelialtumorsBertrandRouty,1,2,3EmmanuelleLeChatelier,4LisaDerosa,1,2,3ConnieP.M.Duong,1,2,5MaryamTidjaniAlou,1,2,3RomainDaillère,1,2,3AurélieFluckiger,1,2,5MeriemMessaoudene,1,2ConradRauber,1,2,3MariaP.Roberti,1,2,5MarineFidelle,1,3,5CarolineFlament,1,2,5VichnouPoirier-Colame,1,2,5PauleOpolon,6ChristopheKlein,7KristinaIribarren,8,9,10,11,12LauraMondragón,8,9,10,11,12NicolasJacquelot,1,2,3BoQu,1,2,3GladysFerrere,1,2,3CélineClémenson,1,13LauraMezquita,1,14JordiRemonMasip,1,14CharlesNaltet,15SolennBrosseau,15CourecheKaderbhai,16CorentinRichard,16HiraRizvi,17FlorenceLevenez,4NathalieGalleron,4BenoitQuinquis,4NicolasPons,4BernhardRyffel,18VéroniqueMinard-Colin,1,19PatrickGonin,1,20Jean-CharlesSoria,1,14EricDeutsch,1,13YohannLoriot,1,3,14FrançoisGhiringhelli,16GérardZalcman,15FrançoisGoldwasser,9,21,22BernardEscudier,1,14,23MatthewD.Hellmann,24,25AlexanderEggermont,1,2,14DidierRaoult,26LaurenceAlbiges,1,3,14GuidoKroemer,8,9,10,11,12,27,28*LaurenceZitvogel1,2,3,5*Immunecheckpointinhibitors(ICIs)targetingthePD-1/PD-L1axisinducesustainedclinicalresponsesinasizableminorityofcancerpatients.WefoundthatprimaryresistancetoICIscanbeattributedtoabnormalgutmicrobiomecomposition.AntibioticsinhibitedtheclinicalbenefitofICIsinpatientswithadvancedcancer.Fecalmicrobiotatransplantation(FMT)fromcancerpatientswhorespondedtoICIsintogerm-freeorantibiotic-treatedmiceamelioratedtheantitumoreffectsofPD-1blockade,whereasFMTfromnonrespondingpatientsfailedtodoso.MetagenomicsofpatientstoolsamplesatdiagnosisrevealedcorrelationsbetweenclinicalresponsestoICIsandtherelativeabundanceofAkkermansiamuciniphila.OralsupplementationwithA.muciniphilaafterFMTwithnonresponderfecesrestoredtheefficacyofPD-1blockadeinaninterleukin-12–dependentmannerbyincreasingtherecruitmentofCCR9+CXCR3+CD4+Tlymphocytesintomousetumorbeds.Cancerimmunotherapyhasbecomehighlysuccessfulagainstanarrayofdistincthem-atologicalandsolidmetastat...
