538|NATURE|VOL554|22fEbRUARy2018LETTERdoi:10.1038/nature25492TGFβdrivesimmuneevasioningeneticallyreconstitutedcoloncancermetastasisDanieleV.f.Tauriello1,2,SergioPalomo-Ponce1,2,DianaStork1,Antonioberenguer-Llergo1,Jordibadia-Ramentol1,MarIglesias2,3,4,5,MartaSevillano1,2,SalesIbiza1,AdriàCañellas1,XavierHernando-Momblona1,2,Danielbyrom1,JoanA.Matarin1,AlexandreCalon1†,ElisaI.Rivas1†,AngelR.Nebreda1,6,AntoniRiera1,7,CamilleStephan-OttoAttolini1&Eduardbatlle1,2,6Mostpatientswithcolorectalcancerdieasaresultofthediseasespreadingtootherorgans.However,noprevalentmutationshavebeenassociatedwithmetastaticcolorectalcancers1,2.Instead,particularfeaturesofthetumourmicroenvironment,suchaslackofT-cellinfiltration3,lowtype1T-helpercell(TH1)activityandreducedimmunecytotoxicity2orincreasedTGFβlevels4predictadverseoutcomesinpatientswithcolorectalcancer.Hereweanalysetheinterplaybetweengeneticalterationsandthetumourmicroenvironmentbycrossingmicebearingconditionalallelesoffourmaincolorectalcancermutationsinintestinalstemcells.Quadruple-mutantmicedevelopedmetastaticintestinaltumoursthatdisplaykeyhallmarksofhumanmicrosatellite-stablecolorectalcancers,includinglowmutationalburden5,T-cellexclusion3andTGFβ-activatedstroma4,6,7.InhibitionofthePD-1–PD-L1immunecheckpointprovokedalimitedresponseinthismodelsystem.Bycontrast,inhibitionofTGFβunleashedapotentandenduringcytotoxicT-cellresponseagainsttumourcellsthatpreventedmetastasis.Inmicewithprogressivelivermetastaticdisease,blockadeofTGFβsignallingrenderedtumourssusceptibletoanti-PD-1–PD-L1therapy.OurdatashowthatincreasedTGFβinthetumourmicroenvironmentrepresentsaprimarymechanismofimmuneevasionthatpromotesT-cellexclusionandblocksacquisitionoftheTH1-effectorphenotype.ImmunotherapiesdirectedagainstTGFβsignallingmaythereforehavebroadapplicationsintreatingpatientswithadvancedcolorectalcancer.Progressionofcolorectalcancer(CRC)generallycoincideswithsuc-cessivealterationsinfoursignallingpathways:WNT,EGFR,p53andTGFβ5,8.Micebearingcompound...
