CancerCellPerspectiveObstaclesPosedbytheTumorMicroenvironmenttoTcellActivity:ACaseforSynergisticTherapiesKristinG.Anderson,1,2,3,4IngunnM.Stromnes,1,2,4,*andPhilipD.Greenberg1,2,3,*1ClinicalResearchDivision,FredHutchinsonCancerResearchCenter,MailStopD3-100,P.O.Box19024,Seattle,WA98109,USA2PrograminImmunology,FredHutchinsonCancerResearchCenter,Seattle,WA98109,USA3DepartmentsofMedicine/OncologyandImmunology,UniversityofWashingtonSchoolofMedicine,Seattle,WA98109,USA4Co-firstauthor*Correspondence:istromne@fredhutch.org(I.M.S.),pgreen@u.washington.edu(P.D.G.)http://dx.doi.org/10.1016/j.ccell.2017.02.008Tcelldysfunctioninsolidtumorsresultsfrommultiplemechanisms.Alteredsignalingpathwaysintumorcellshelpproduceasuppressivetumormicroenvironmentenrichedforinhibitorycells,posingamajorobstacleforcancerimmunity.Metabolicconstraintstocellfunctionandsurvivalshapetumorprogressionandimmunecellfunction.Inthefaceofpersistentantigen,chronicTcellreceptorsignalingdrivesTlympho-cytestoafunctionallyexhaustedstate.HerewediscusshowthetumoranditsmicroenvironmentinfluencesTcelltraffickingandfunctionwithafocusonmelanoma,andpancreaticandovariancancer,anddiscusshowscientificadvancesmayhelpovercomethesehurdles.IntroductionSolidtumorscommonlyarisefromgeneticmutationsindriveroncogenesandtumorsuppressorgenesthathaveprofoundconsequencesoncelldifferentiation,proliferation,survival,andgenomicstability.Duringcancerprogression,tumorcellsalternormaldevelopmentalprocessestoorchestrateasupportivebutovertlyimmunosuppressivetumormicroenvironment(TME)comprisedofimmunecells,fibroblasts,andendothelialcells,oftenembeddedwithinarobustextracellularmatrix(ECM)(Ha-nahanandCoussens,2012;Stromnesetal.,2014b;Whiteside,2008).Fromtheformationoftheearliestpre-invasivelesiontometastaticspread,theTMEcansupportangiogenesis,tumorprogression,andimmuneevasionfromTlymphocyterecogni-tion,aswellasdictateresponsetocancertherapy.Despitethesignificantobstaclesthattumor-reactiveTlymphocytesfaceinsolidtumors,accumulatingevidenceindicat...
