5-Acquired and intrinsic resistance in cancer immunotherapy

MOLECULARONCOLOGY8(2014)1132e1139

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Acquiredandintrinsicresistanceincancerimmunotherapy

SanderKelderman,TonN.M.Schumacher,JohnB.A.G.Haanen*

TheNetherlandsCancerInstitute,Plesmanlaan121,1066CX,Amsterdam,TheNetherlands

ARTICLEINFOABSTRACT

Articlehistory:

Received13June2014Accepted13July2014Availableonline24July2014Keywords:

CancerimmunotherapyImmuneresistanceT-cellresponse

Anumberofimmunotherapies,inparticularimmunecheckpointtargetingantibodiesandadoptiveT-celltherapies,arestartingtotransformthetreatmentofadvancedcancers.Thelikelihoodtorespondtotheseimmunotherapiesdiffersstronglyacrosstumortypes,withresponseratesforcheckpointtargetingbeingthehighestinadvancedmelanoma,renalcellcancerandnon-smallcelllungcancer.However,alsonon-responsivenessisobserved,indicatingthepresenceofintrinsicresistanceornaturallyacquiredresistance.Inaddition,asubgroupofpatientsthatdoinitiallyrespondtoimmunotherapywilllaterrecur,therebyalsopointingtowardsaroleoftherapy-inducedacquiredresistance.

Here,wereviewourcurrentunderstandingofbothintrinsicandacquiredresistancemech-anismsincancerimmunotherapy,anddiscusspotentialstrategiestoovercomethem.ª2014FederationofEuropeanBiochemicalSocieties.PublishedbyElsevierB.V.Allrights

reserved.

1.Introduction

Formanytumortypes,includingmelanoma,renalcellcancer,coloncancer,ovariancancer,andsomesubtypesofbreastcancer,thepresenceoflymphocyticin?ltrateswithinthetu-morishighlycorrelatedwithimprovedoutcome(Alexeetal.,2007;Clementeetal.,1996;Erdagetal.,2012;Galonetal.,2006;Hwangetal.,2012;Mahmoudetal.,2011;Nakanoetal.,2001;Zhangetal.,2003).Thesein?ltratesmostlyconsistofCD4þandCD8þT-cells,andespeciallyformela-nomaithasbeenwellestablishedthatpartoftheseT-cellsrecognizetumor-associatedantigens(Coulieetal.,1994;Kawakamietal.,1994).Thefactthatthesecellscanhavedirecttumoricidalpotentialiswellillustratedbytheclinicaleffectsofadoptivetransferofexvivoexpandedtumor-in?ltratinglymphocytes(TIL)inmetastaticmelanoma

patients.Inseveralsmallclinicaltrials,responseratesvaryingfrom40%to70%havebeenobservedinhighlyselectedmeta-staticmelanomapatients(Dudleyetal.,2010,2008).Inamorerecentintent-to-treatanalysisinaTILtrialformelanoma,aresponserateof30%hasbeenreported(Besseretal.,2013).Withinthesestudies,theabsolutenumbersofCD8þT-cellsinfusedisstronglycorrelatedwithresponsetotreatment,sug-gestinganimportantroleforMHCclassIrestricted,cytotoxicT-lymphocyte(CTL)mediatedtumorkilling(Besseretal.,2013;Radvanyietal.,2012).DirectevidenceinsupportofsucharolehasbeenobtainedthroughtheadministrationofTILproductsenrichedforCD8þT-cells,whichshowedaresponseratecomparabletothatseenwithunselectedTILproducts(Dudleyetal.,2013).Inadditiontotumor-reactiveCD8þT-cells,itisclearthatTILproductscanalsocontainCD4þT-cellpopulationsthataretumor-reactive,andthereis

*Correspondingauthor.

E-mailaddress:j.haanen@nki.nl(J.B.A.G.

Haanen).http://wendang.chazidian.com/10.1016/j.molonc.2014.07.011

1574-7891/ª2014FederationofEuropeanBiochemicalSocieties.PublishedbyElsevierB.V.Allrightsreserved.

MOLECULARONCOLOGY8(2014)1132e1139

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evidenceforananti-tumoraleffectofsuchtumor-reactiveCD4þpopulationsinmelanomaandcholangiocarcinoma(Hunderetal.,2008;Tranetal.,2014).

Asecond,muchmorewidelyused,groupofimmunother-apeuticstrategiesthattargetthesamecellularcompartmentfocusesontheadministrationofantibodiesthatbindtoim-munecheckpointmolecules,thereby(re)activatinganendog-enoustumor-speci?cT-cellimmuneresponse.Administrationofipilimumab,anantibodythatbindstheinhibitoryreceptorcytotoxicT-lymphocyteantigen4(CTLA-4)onT-cells,hasshownafourmonthincreaseinmedianoverallsurvivalinphaseIIItrials,leadingtoFDAandEMAapproval(Hodietal.,2010;Robertetal.,2011).Ananalysisofalargecohortofmelanomapatientstreatedfollowingthisregistrationshowsalong-termsurvivalin20e25%oftreatedmetastaticmelanomapatients(Prietoetal.,2012),anumberthatcomparesfavorablytothe8e10%seenpreviouslyinpa-tientstreatedwithchemotherapy.Morerecently,objectiveresponseratesupto50%havebeenreportedinphaseI/IItrialstestingantibodiesthattargetanothercheckpointmolecule,programmedcelldeathprotein1(PD-1)oritsligand(PD-L1).Importantly,clinicalresponsesuponPD-1ePD-L1targetinghavebeenobservedinmalignanciesotherthanmelanoma,suchasrenalcellcarcinoma(RCC)andnon-smallcelllungcancer(NSCLC)(Brahmeretal.,2012;Hamidetal.,2013;Topalianetal.,2012).

Theseencouragingclinicalresultshaverightfullyputimmunotherapyattheforefrontofoncologicalpractice.Nevertheless,itisimportanttonotethatasubstantialnumberofpatientsstillderivenooronlylimitedbene?tforreasonslargelyunknown,sometimesatthecostofseveretoxicities.Thedisparityinresponseratesobservedbetweendifferentimmunotherapeutictreatmentmodalities,butalsoacrosstu-mortypesstronglysuggestsaroleforimmuneresistance.Furtherevidenceforsuchresistancecomesfrompatientstreatedwithimmunotherapywhoexperienceaninitial

decreaseinoveralltumorburdenbuteventuallysuccumbtodiseaserecurrence.Inthefollowingsectionswedescribetherelevanceofdifferentclassesofimmunotherapyresistanceinoncologyandcontrastthiswiththerapyresistanceseenwithtargetedtherapies.Furthermore,wedescribethestrate-giesthatmaybetakentoobtainabetterunderstandingofimmunotherapyresistance,andhowthisknowledgecanbeusedclinically.

2.Requirementsforanoptimalanti-tumorT-cellresponse

TounderstandatwhichlevelsresistancetoTcell-basedcan-cerimmunotherapymayoccur,itisimportantto?rstdescribethekeyelementsthatarerequiredforasuccessfulT-cellresponsethatleadstocancerregression.Todoso,wesubdi-videthisprocessintothreediscretesteps(Figure1).

First,T-cellsneedtobeproperlyactivatedbyprofessionalantigen-presentingcells(APCs)inperipherallymphoidorgans.Forthistooccur,twothingsarerequired:A).Dendriticcells(DCs)needtodisplaytumorantigens(derivedfromapoptoticornecrotictumorcells)inthecontextofMHCclassIorIIforwhichanantigen-speci?cT-cellrepertoireispresent.B).TheseDCsneedtohavereceivedmaturationsignalsthatinstructthedevelopmentofaneffectorT-cellresponse,ratherthanT-cellanergyortheexpansionofregulatoryT(Treg)cells.

Second,followingpriminginperipherallymphoidorgans,theactivatedT-cellsneedtohometothetumor,extravasatethroughtheendotheliumandin?ltrateviathesurroundingstromaltissueintothetumorbeforetheycanbindtotheirtarget.Thisbothrequirescertainphenotypiccharacteristics,suchasexpressionofchemokinereceptors,ontheT-cellsandtheexpressionofcelladhesionmolecules/chemokinesbythevascularendotheliumforcellstopassthe

endothelial

Figure1eKeyelementsforaneffectiveanti-tumorT-cellresponse.Thedevelopmentofaneffectiveanti-tumorT-cellresponsefollowsthreedistinctsteps:1.)Primingandactivationofna