ContentslistsavailableatScienceDirectSeminarsinCancerBiologyjournalhomepage:www.elsevier.com/locate/semcancerReviewImmunecheckpointsinthetumormicroenvironmentSalmanM.Toora,VarunSasidharanNaira,JulieDecocka,EyadElkorda,b,*aCancerResearchCenter,QatarBiomedicalResearchInstitute(QBRI),HamadBinKhalifaUniversity(HBKU),QatarFoundation(QF),POBox34110,Doha,QatarbInstituteofCancerSciences,UniversityofManchester,Manchester,UnitedKingdomARTICLEINFOKeywords:ImmunecheckpointsImmunecheckpointinhibitorsTumormicroenvironmentABSTRACTInteractionsbetweenimmunecheckpoints(ICs)andtheirligandsnegativelyregulateTcellactivationpathwaysinvolvedinphysiologicalimmuneresponsesagainstspecificantigens.ICsandtheirligandsarefrequentlyup-regulatedinthetumormicroenvironment(TME)ofvariousmalignancies,andtheyrepresentsignificantbarriersforinductionofeffectiveanti-tumorimmuneresponses.SeveralICinhibitors(ICIs)havebeendeveloped,withsomecurrentlyinclinicaltrialsandothershavebeenapprovedforthetreatmentofdifferentcancers.However,tumorcellsareabletocounteracttheactivityofICIsandcancommissionadditionalinhibitorypathwaysviaexpressionofotherICs/ligandswithintheTME.ThisreviewdiscussestheexpressionofvariousICs/ligandsintheTMEandtheirimpactontumorimmuneevasion.Additionally,wediscussvariousregulatorymechanisms,includinggeneticandepigenetic,andothermodulatoryfactorsincludinghypoxiaandthepresenceofim-munosuppressivepopulationsintheTME,whichresultinupregulationofICsinvariouscancers.Moreover,wediscusstheprognosticsignificanceofICsandtheirligands,andthepotentialstrategiestoenhancetreatmentresponsestoICIs.ThisreviewaimstoadvanceourcurrentknowledgeontheroleofICsintheTMEandtheclinicalbenefitsoftargetingthem.1.IntroductionImmunecheckpoint(IC)pathwaysattenuateTcellresponsestopreventautoimmunityandmaintainimmunehomeostasis.However,tumorscanhijacktheseimmune-inhibitorypathwaystoattainimmuneresistanceagainsttumorantigen-specificTcells.ICsandtheirligandsarefrequentlyupregulatedinthetumormicroenvironment(TME)ofvariousmalignanc...
