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ClaudiaCantoni(a,b,c),KorneelGrauwet(d),GabriellaPietra(a,e),MonicaParodi(a),Maria
CristinaMingari(a,b,e),AndreaDeMaria(b,e,f,),HermanFavoreel(d,),MassimoVitale(e,
)
(a)DepartmentofExperimentalMedicine(DIMES),UniversityofGenova,Genova,Italy
(b)CenterofExcellenceforBiomedicalResearch (CEBR),UniversityofGenova,Genova,
Italy
(c)IstitutoGianninaGaslini,Genova,Italy
(d)LaboratoryofImmunology,DepartmentofVirology,ParasitologyandImmunology,Facultyof
VeterinaryMedicine,GhentUniversity,Belgium
(e)IRCCSAOUSanMartinoISTGenova,Genova,Italy
(f)DepartmentofHealthSciences(DISSAL),UniversityofGenova,Genova,Italy
()Theseauthorsshareseniorauthorship
KEYWORDS:NKcellssolidtumortumormicroenvironmenttumorescapeimmunotherapy
virotherapy
Correspondence to:
MassimoVITALE:massimo.vitale@hsanmartino.it
ClaudiaCANTONI:claudia.cantoni@unige.it
ACKOWLEDGEMENTS:
ThisworkwassupportedbygrantsawardedbyAIRC:IGprojectn.15428(M.V.);Ministerodella
Salute: Ricerca Finalizzata RF20102316197 (A.D.M),RFIG20081200689 (M.C.M.);
ProgrammanazionalediricercasullAIDS,Accordidicollaborazionescientifica45G.11,40H69
(A.D.M.);MIURProgettodiAteneo2014(A.D.M);theSpecialResearchFundofGhentUniversity
(grants01J29110,01J11611and01G01311)(H.F.);F.W.O.Vlaanderen(grants1.5.077.11Nand
G.017615N) (H.F.); the Hercules Foundation (grant AUGE035) (H.F.), and an international
mobilitygrantfromF.W.O.Vlaanderen(H.F.).
ABSTRACT
AlthoughNKcellsareendowedwithpowerfulcytolyticactivityagainstcancercells,theirrolein
differenttherapiesagainstsolidtumorshasnotyetbeenfullyelucidated. Theirinteractionswith
variouselementsofthetumormicroenvironmentaswellastheirpossibleeffectsincontributingto
and/orlimitingoncolyticvirotherapyrenderthispotentialimmunotherapeutictoolstilldifficultto
exploitatthebedside.Herewewillreviewthecurrentliteraturewiththeaimofprovidingnewhints
tomanagethispowerfulcelltypeinfutureinnovativetherapies,suchastheuseofNKcellsin
combinationwithnewcytokines,specificmAbs(inducingADCC),TyrKinaseinhibitors(TKi),
ImmunomodulatoryDrugs(IMiDs),and/orthedesignofoncolyticvirusesaimedatoptimizingthe
effectofNKcellsinvirotherapy.
INTRODUCTION
Immediatelyaftertheirdiscovery,NKcellscaughttheattentionofmanyresearchersfortheirability
tokillaratherwiderangeoftumorcelltypes.Fromtheoutset,NKcellsappearedasareadyto
use cell population that could be employed against a variety of tumors without the need for
selectingspecificclones,asvirtuallyallNKcellswereendowedwithaMHCunrestrictedwide
specificityfortumorcells.Theexploitationofthesecellsforeffectiveimmunotherapyseemedan
achievablegoalandpromptlystimulatedtoinvestigatethemechanismsregulatingtheirfunction.
ThebrilliantintuitionofKlasKarre(whopostulatedthatNKcellswereabletokillonlywhenthey
missedtherecognitionofautologousMHCImoleculesontargetcells)andthepioneeringstudies
ofdifferentgroupsledquiterapidlytodefinetherecognitionmechanismofNKcells[14].Human
NKcellsweredemonstratedtorecognizeandkilltumorcellswithdownregulatedHLAImolecule
expressionbyusingacomplexgroupofHLAIspecificinhibitoryreceptors(KIRsandNKG2A)
andseveralmajoractivatingreceptors(includingNKG2D,DNAM1andtheNaturalCytotoxicity
tissue[1517].Aplethoraofsolublefactorsandcellularnetworks,aswellaspeculiarphysical
and/orchemicalconditions,canaffecttheabilityofNKcellstorecognizeandkilltumorcells,or
influencetheirabilitytomigratefromthebloodtothetumorsite.Itshouldalsobeconsideredthat
NKcellspresentinthetumormicroenvironmentmaydirectlyoriginatefromthelocalperipheral
tissues.Inthiscontext,recentstudieshaveshownthatdifferentperipheraltissuesandsecondaryor
tertiarylymphoidorgansmaycontainmembersofanNKrelatedfamilyofinnatelymphoidcells
(ILCs).Thesecellscanusetheirreceptorstofulfillpeculiarfunctions,differentfromkillingtumor
cells[1821].ThisstillexpandingheterogeneousgroupofILCsinclude:1)conventionalcytotoxic
NKcells(recentlyproposedtobedefinedascytotoxicILC1),whichconstitutethelargemajorityof
peripheralblood(PB)NKcells(butarealsopresentintissues), releaseIFN andTNF,and
functionallyinteractwithdifferentAPC; 2)poorlycytolyticCD56brightCD16dim NKcells,which
constitutethelargemajorityoflymphnodal(LN)NKcells(butarealsopresentintissuesandPB),
releaseprimarilyIFNandGMCSF,andinteractwithDC,participatingtotheinductionofTh1
polarizationinLN;3)NKp44+NK22cells(includedintheILC3group),whicharelocatedinthe
MALT,releaseIL22andareinvolvedinthemucosalhomeostasisanddefense;4)decidualNK
cells,whichproduceIFN,IL8,IP10,SDF1andVEGF,andarethoughttoplayanimportant
roleintheplacentaldevelopmentandinductionofmaternalfetaltolerance[22].This complex
repertoireofNKcellsubsetswiththeirdifferentrelativefunctionsshouldalsobeconsideredto
betterexploittheirfunctionalcapabilitiesinoldandnewtherapeuticapproaches,eithertoidentify
newpossiblebeneficialsynergies,oreventorecognizestillunnoticedNKdrivenunwantedeffects.
AnotherwellknownfunctionofNKcellshasalsobecomeimportantfortumortherapy,namely
theirabilitytorecognizeandkillvirusinfectedcells[56].ThisaspectofNKcellbiologyhascome
intoplaybythedesignofstrategiestotargettumorcellsusingoncolyticvirotherapy[23].Inthis
context, NK cells may represent a double edged sword as the NKmediated killing of virally
infectedtumorcellsmayeitherpotentiatetheantitumoreffectofvirusesorlimittheinfection
spreadwithinthetumor[24,25]andthereforepreventsuccessfromoncovirotherapy.
Thus,incontrasttotheinitialidea,theexploitationofNKcellsforthecureofcancerisquite
complicatedandrequiresmultipleapproachesthatshouldbeadaptedtothetypeoftumorand/or
adoptedtherapeuticstrategy.
NKCELLSANDTHETUMORMICROENVIRONMENT
ThepresenceofanNKcellinfiltratehasbeenobservedtovariableextentinseveraltypesofsolid
tumorsincludingmelanomas,gastrointestinalstromaltumors(GIST),colorectal,renal,lungand
breastcancers [2634].Insomecases,GISTandrenalcarcinomalungmetastasesdisplayedhigh
levelsofNKcellinfiltration,whichcorrelatedtoabetterprognosis[29,32].Thetypeandthesize
oftheNKcellinfiltrateinneoplastictissuescandependonseveralfactors,includingthespecific
chemokinesproducedinthetumormicroenvironmentandthechemokinereceptorpatternexpressed
bydifferentNKcellsubsets.Inlungandbreastcancersithasbeenshownthat poorlycytotoxic
CD56brightNKcellsfrequentlyrepresentthemajorNKcellsubsetrecruitedatthetumorsite[31,33].
ThesetumorsexpressedhighlevelsofmRNAcodingforCXCL9andCCL19,twochemokinesare
recognizedbychemokinereceptorsselectivelyexpressedbyCD56bright cells(CXCR3andCCR7
respectively). Ontheotherhand,somestudiesalsoreportasignificantpresenceofCD56 dim NK
cellsinlungtumorsandinmelanomanodalmetastases[30,34].Inthelattercase,cellsfromtumor
tissueweredemonstratedtoproduceIL8,which,indeed,canpreferentiallyattractCD56 dim NK
cells.AnotherimportantissueisthelocationoftheNKcellinfiltratewithinthetumortissue. In
colorectalcancerstudiesithasbeenrecentlyshownthat,inspiteofthepresenceofchemokinesthat
areabletorecruitbothCD56brightandCD56dimNKcellsubsets,NKcellsarelocalizedwithinthe
stroma,ratherthanbeingindirectcontactwithneoplasticcells[35].AsimilarNKcelllocalization
melanoma metastases, have been shown to prevent the IL2induced upregulation of NKp44,
DNAM1andNKp30receptors.Thiseffectwasmediatedbothbydirectcelltocellcontactandby
PGE2release[36].AsimilarbehaviorhasbeenobservedinTAFsderivedfromcolorectalcancer
(HCC)andhepatocellularcarcinoma[50,51].TherelevanceofNKcellfibroblastinteractionsin
vivoisfurthersuggestedbythefindingthatinmelanomametastasesandGISTlesionsNKcellscan
localizeinproximitytofibroblastssurroundingtumornests[32,36,37].
Asubstantialsuppressiveroleisalsoexertedbytumorcellsthroughseveralmechanisms.Wehave
recentlydemonstratedthatmelanomaderivedprimarycelllines couldinhibittheexpressionof
several activating NK receptors, thus decreasing NK cellmediated killing of tumor cells. This
effectwasmediatedbyIDOexpressionand/orPGE2release[52].Differenttumorcelltypescan
releaseMHCclassIchainrelatedgeneA(MICA),aligandforNKG2Dactivatingreceptor,by
shedding,thusinducingdownregulationorunresponsivenessofNKG2D[53].Ovariancancercells
caninterferewithNKcellfunctionsbyinducingNKG2Ddownregulationthroughthereleaseof
macrophageinhibitoryfactor(MIF),orbyexpressingtheglycoproteinMUC16,whichcaninhibit
synapseformationbetweenNKcellsandtumorcells[54,55].Tumorcellscanalsoaffecttheability
of NK cells to infiltrate the tumor. It has been recently shown that neuroblastoma cells could
modulatethechemokinereceptorrepertoireofNKcellsthroughTGF production[56].Tumor
cellsfromdifferentcancerscanreleaseB7H6,aligandforNKp30activatingNKreceptor,through
ectodomainsheddingmediatedbycellsurfaceproteasesADAM10andADAM17,thusreducing
NKcellmediatedrecognition[57].Finally,hypoxia,aconditionfrequentlyassociatedtothetumor
microenvironment,caninfluencetheimmuneresponseagainstthetumor. AsfarasNKcellsare
concerned, we have recently demonstrated that the hypoxic status can deeply inhibit both the
expressionandthefunctionofdifferentactivatingreceptors.NKcells,however,werenotaffected
byhypoxiaintheirabilitytoperformAntibodyDependentCellmediatedCytotoxicity(ADCC)
[58].
TheantitumoractivityofNKcellsandtheirprolongedinteractionwithcancercellscanalsoexerta
selectivepressurethatmayfavorthegenerationoftumorcellsdisplayinganabnormalexpressionof
ligandsspecificforactivatingorinhibitoryNKcellreceptors.Ourgrouphasshownthatinvitroco
cultureofmelanomacellswithNKcellsresultedinanIFNdependentupregulationofHLAI
expressiononmelanomacells,whichwasresponsibleforthe(acquired)resistanceofthesecellsto
NKmediated killing [26]. Tumor cells may also escape from NKmediated recognition by
modulating cell surface expression of ligands for activating NK receptors, as in the case for
NKG2Dligands [53].ActivatingreceptorsexpressedonNK cells maybeimportantfortumor
immunoediting. Forexample,ithasrecentlybeenshownthat tumorsthatdevelopedinNKp46
deficientmiceexpressedhigherlevelsofNKp46ligandsascomparedtotumorsthatdevelopedin
wildtypemice[59].TheupregulationofligandsabletotransmitinhibitorysignalstoNKcells
representsanotherpossiblemechanismoftumorescapefromNKcellantitumoractivity.Inthis
context,ithasbeenrecentlyshownthatProliferatingNuclearCellAntigen(PCNA),frequently
overexpressedindifferenttumortypes,canengagetheactivatingNKp44receptorandinducea
paradoxicalinhibitorysignal[60].NKcellcytotoxicfunctioncanalsobeinhibitedthroughthe
engagementofCD300a,aninhibitoryreceptorrecognizingphosphatidylserineexposedoncertain
tumorcells[61].
ROLEOFNKCELLSINTHERAPIESTARGETINGSOLIDTUMORS
Althoughcancerimmunotherapystrategies havemainlyreliedontheactivityoftumorantigen
specificTcells,inrecentyearsthetherapeuticuseofNKcellstotreatmalignancieshasrapidly
movedforward[62,63].Inthissection,wewillreviewtheNKcellbasedtherapeuticapproaches
that are being currently explored in either clinical or preclinical contexts. These approaches
include: a) invivo stimulationof endogenousNKcellsagainsttumors(bytheuseofcytokines,
antibodiesorimmunomodulatorydrugs); b) adoptivetransferofinvitroexpandedandactivated
NKcells(bothinautologousandallogeneicsettings);c)geneticmodificationofNKcells.
ThestimulationofdifferentNKcellfunctions,includingcytotoxicityagainsttumorcellsandIFN
productioncanbeinducedbytheuseofseveralcytokinesincludingIL2,IL15,IL12,IL18and
interferons .TheadministrationofrecombinantIL2resultedinremarkablecytokinerelated
toxicity(suchasvascularleaksyndromeandhearttoxicity)andlimitedclinicalbenefits(possibly
duetotheinductionofTregs)[8,64],Theseissuespromptedthesearchforothercytokinesableto
effectivelyboostNKcells.IL15,IL12,andIL18arebeingevaluatedbothinpreclinical[65]and
clinicalcancermodels [6668].Whilethesecytokinesdisplaylimitedanticanceractivitywhen
usedassingleagents,arecentreportinmiceshowedthatpoorlyfunctionalNKcells,infiltrating
MHCclassIdeficienttumors,couldbeeffectivelyboostedbythecombineddeliveryofIL12and
IL18[69].Thisstudywarrantstheevaluationofthepossibleuseofthiscytokinecombinationin
humans.
TheefficacyofNKcellsintargetingtumorcellsmaybealsoincreasedbyinterveningwiththe
inhibitoryinteractionbetweenKIRsandHLAImolecules,thatarepossiblyexpressedontumor
cells.Inthiscontext,ahumanmonoclonalantibody(mAb)(17F9/IPH2101)abletoblockKIRs
that recognize HLAC molecules has been recently developed [70]. The use of lirilumab (a
recombinantversionof17F9)hasbeenshowntoincreaseNKcellmediatedkillingofHLAC
positivetumorcellsinananimalmodel[71].
The therapeutic potential of PB NK cells can also be exploited for the treatment of both
hematologicalandsolidtumors thankstotheirabilitytomediateADCCthroughcrosslinkingof
CD16.TheNKcellmediatedADCChasbeensuggestedtoberelevanttothetherapeuticeffectof
Rituximab or Cetuximab in mAbbased tumortargeted therapies [72]. Along this line, several
reports indicated that NK cell function could be harnessed by the administration of mAbs
recognizingtumorantigens[73].
Besidescytokinesandantibodies,severalimmunomodulatorydrugsareabletoreinstateNKcell
effector function either directly or indirectly. Among these drugs, Lenalidomide (a synthetic
derivativeofThalidomide)hasbeenextensivelytestedinpatients.Interestingly,Lenalidomidenot
onlydirectlyactsonNKcells(bypromotingboththeirnaturalcytotoxicityandADCCfunction)
butitcanalsosensitizetumorcellstoNKmediatedkilling(byupregulating theexpressionon
tumor cells of ligands recognized by activating NK receptors) [63]. Along this line, several
chemotherapeuticdrugs(suchasetoposideanddacarbazine),histonedeacetylasesinhibitors(such
asVPA),HSP90inhibitorsandproteasomeinhibitorsareabletoinducetheexpressionofTRAIL
andNKG2DLsontumorcells[74].Finally,alsotheTKiarebeingevaluatedfortheireffectson
theNKmediatedtumorcellkilling[reviewedin74].TheinterestontheTKiwasstimulatedbythe
initial observation that Imatinib therapy of GIST patients could induce an increased NK cell
functionthatcorrelatedwithapositivetherapyresponse.Thesubsequentstudiesledtoarather
complex picture showing that different members of the TKi family can modulate the NK cell
functionthroughcombined,evencontrasting,actions,rangingfromthesuppressionofTregsorthe
enhancementoftheNK/DCcrosstalk,tothereductionofNKG2DLexpressionontumorcells.
PerhapsthemostinterestingapproachtoincreasetheefficacyofNKcellsisthesearchforpossible
synergiesbetweentheabovedescribedstrategies.Forexample,thesynergisticeffectoftheKIR
blockade by Lirilumab and the Rituximabmediated ADCC has been recently tested in a KIR
transgenic murine model [71]. A clinical trial using IPH2101 antiKIR mAb combined with
lenalidomideisinprogressinmultiplemyeloma[75].
The early studies employing ex vivo lymphokineactivated killer (LAK)cells showed noclear
benefit of this form of therapy compared with IL2 administration [8, 76]. In a recent study,
Rosenberg and colleagues [77] reported that a lymphodepleting chemotherapy, consisting of
fludarabineandlowdosecyclophosphamide,mightpromotehomeostaticexpansionofautologous
adoptivelytransferredNKcells.Interestingly,thesecellsexpressedCD16andthuscouldmediate
ADCCwithoutcytokineactivation[77].
AutologousNKcellsmaybeinhibitedbyrecognitionofselfHLAImoleculesexpressedbytumor
cells. Therefore, the use of allogeneic NK cells in a KIR/HLAI mismatch setting may be
tentatively appealing, especially in view of the promising results obtained with HSCT in
hematologic malignancies [12, 13]. The adoptive transfer of allogeneic NK cells is under
investigationinsolidtumors,aswitnessedbyrecentclinicaltrialsevaluatingthesafetyandthe
efficacy of this approach [7880]. However, the suppressive effects related to the local
microenvironmentaswellastheuseofmatureNKcells(insteadofHSCT)maycomplicatethe
issue.
The poor ability of transferred NK cells to home to tumor sites represents another important
negativefactorthatmightexplain,atleastinpart,theweakantitumoreffectofadoptiveNKcell
therapyagainstsolidmalignancies.Recently,ithasbeenshownthatNKcells,whenexposedtoIL
15andglucocorticoids,expresshighlevelsofCXCR3thusincreasingtheirpotentialtoinfiltrate
CXCL10+tumors[81].
Finally,anotherintriguingnewtherapeuticstrategy,notyetarrivedinclinicaltesting,isthetumor
targeting with genetically modified NK cells engineered to express chimeric antigen receptors
specificfortumorantigens(CAR)[82]orcytokines.
ONCOLYTICVIROTHERAPYANDSOLIDTUMORS
Overthepasttwodecades,virotherapyhasreceivedincreasingattentionwithregardtoitspotential
application towards (particularly hard to treat) cancers with very poor prognosis, such as
glioblastoma.Thegeneralideabehindoncolyticvirotherapyistheuseof(geneticallyengineered)
virusesthatselectivelyreplicateinandlysetumorcells,whilesparinghealthytissue.Remarkably,
thisapproachmaybeparticularlyinterestingalsointhecureofsolidtumors,sincevirusreplication
andspreadmayenabletheoncolyticvectortopenetratethetumor,andtherebyenhanceimmune
andtherepauticdrugpenetrationincombinationtherapies(insertoldreference86and87;Woller,
2014;Chiocca,2014)..
Sincethefirstapprovalofanoncolyticvirus,adenovirusbasedoncolyticvirusH101(Oncorine),
forcancertreatmentinChinain2005,inparticularforheadandneckcancerincombinationwith
cisplatinbasedchemotherapy,thefieldis rapidlymovingforward(YuW.,2007,CancerDrug
targetsClinicaltrialswithoncolyticadenovirusinchina)(XiaZJ,AiZheng,2004)(GarberK,
2006Journalofnationalcancerinstitute)(insertoldreference83,PolJ.,2014).Thisisillustrated
bydifferentoncolyticvectorscurrentlyindifferentstagesofclinicaltrials,asshownintable2.
OncolyticadenovirusCG0070,modifiedtoexpressGMCSFundercontrolofthehumanE2F1
promotor,isbeingpreparedforphaseII/IIIclinicaltrialstotreatinvasivebladdercancerandhas
providedpromisingresultsinphaseItesting.InphaseItesting,atotalof81%oftreatedpatients
respondedtothetreatmentandthemaximumtolerateddosewasnotreached,demonstratingthe
slumberingpotentialofoncolyticvirotherapy(BurkeJM,2012,J.Urol).
A broad range of oncolytic viral vectors (based on HSV1, reovirus, adenovirus, rhabdovirus,
parvovirus,Newcastlesdiseasevirus,vesicularstomatitisvirus,vacciniavirusandmeaslesvirus)
arebeingassessedinrecentlylaunchedphaseI/IItrialstotreatavarietyofsolidcancers.The
oncolyticvirusesParvOryx,NDVandReolysinarenaturallyoccurringvirusesselectedduetotheir
oncolyticantitumorpotencyandabilitytopreferablytargetandreplicateintumorcells,whilstother
oncolyticviruses,suchasMVNIS,arebasedonattenuatedlaboratorystrainvirusesreportedto
preferably replicate in and lyse tumor cells (MVNIS: Dingli D., 2004, Blood )(ParvOryx:
Geletneky,BMCCancer,2012)(NDV:Mansour,M,JournalofVirology,2011)(Reolysin:Galanes
E. Molecular therapy, 2012). Several oncolytic viruses that are being developed to treat solid
tumorshavebeengeneticallymodifiedtoincreasetumorselectivity.TheoncolyticvirusColoAd1
Wojton,2010,CytokinegrowthfactorRev.).Thisinterlockedmeshworkofmatrixproteinsformsa
physical barrier that not only suppresses access of NK cells and other immune cells, but also
hindersspreadandpenetrationoftheoncolyticvirus,leadingtosuboptimaltherapeuticeffects.In
linewiththis,virusspreadinsolidtumorswasreportedtobelimitedtodiscretetumorareasupon
exvivoinfectionofsolidtumorswithNewcastlesdiseasevirus,andinclinicaltissuesfrompatients
treatedwithG207,anHSV1basedoncolyticviruswithcompletedphaseI/IItrials(Yaakov,2012,
Journalgeneralvirology)(MarkertJM,2009,MolTher).Inthisrespect,theoncolyticadenovirus
basedvectorVCN01wasdesignedtodegradehyaluronicacid,amajorconstituentofextracellular
tumor matrix, via expression of the PH20 hyaluronidase. In mice with prestablished tumors,
expression of PH20 hyaluronidase by an oncolytic virus following intratumoral and systemic
administration has been reported to increase efficacy and improved spread within the tumor,
comparedtotheemptyvirusbackbone(GuedanS,MolTher,2010).PreclinicaltrialswithVCN01
inmiceandhamstersalsoprovidedpromisingresults,supportingselectivity,safetyandantitumor
activityofVCN01(RodriguezGarcia,2015,ClinCancer).
ONCOLYTICVIROTHERAPYANDNKCELLS
Theinteractionofoncolyticviruseswiththehostimmunesystemisparticularlydelicateandmay
have a critical impact on the therapeutic efficacy. On the one hand, oncolytic vectortriggered
immuneresponsesmaybeessentialelementsoftheantitumoreffectsofthetherapy.Ontheother
hand,prematureclearanceoftheselfreplicatingoncolyticvectorbythehostimmuneresponsemay
severelylimittherapeuticpotential[25].Hence,oneofthemostimportantchallengestowardsthe
generationofsuccessfulselfreplicatingoncolyticviralvectorsistofinetunetheinteractionofthe
vector with the host immune system in such a way that beneficial vectortriggered antitumor
immuneresponsesaremaximizedwhileallowingsufficienttimeforthevectortoreplicateand
spreadbeforebeingeliminatedbytheimmuneresponse.
ParticularlyimportantplayersinthisdelicatebalanceareNKcells,displayingbothpotentanti
tumorandantiviralactivity.
NaturalKillercellvirusinteraction.
TheinteractionofviruseswithNKcellsfindsitsframewithinthecoevolutionaryadaptationofthe
immunesystemtoinvadingpathogens.Afterthefirstcharacterizationoftheirmechanismofaction
andtheobservationoftheinvasive,severe,disseminatedclinicalcourseofotherwiselocalizedviral
infections(e.g.herpesviruses)inpatientswithNKcelldeficiencies[88,89],NKcellshavebeen
recognizedasarelevantfirstlinedefenseagainstviruses.Thisoriginalviewhasbeenradically
upgradedinrecentyears,leadingtotheadditionofseveralNKcellfunctionalfeatures including
memorylikeactivitythroughselectivesubsetexpansionuponviralinfection(HCMV,MCMV,
Chikungunya,Hantavirus)andinherentregulationofNCRexpression/function[90,91].
NK cells can sense infected cells either through direct interaction with pathogenassociated
molecularpatternsviaTolllikereceptors,orthroughrecognitionofviraland/or(virusinduced)
cellularligandsofmajoractivatingNKcellreceptors.Suchactivatinginteractions,combinedwith
thereducedengagementofinhibitoryNKreceptorsduetoafrequentlydecreasedsurfaceHLAI
expressiononinfectedcells,caninduceNKcellcytotoxicactivityandcytokinesecretion.
NKcellsdirectlyinteractwithandbindtoviralglycoproteinsthroughtheNCRs(NKp46,NKp30,
NKp44)asdescribed,forexample,forinfluenza,WestNile,anddengueviruses[9295](seeTable
3).Inaddition,NCRsrecognizestillundefinedvirusinducedcellularligands.Whethersomeof
theseligandscouldbesharedwithtumorcellsispoorlyknown,eveniftherearehintssuggesting
thatanewlyidentifiedNKp44ligand,21speMLL5,couldbebothexpressedbytumorcellsand
inducedonTcellsbyHIVgp41peptides.Alongthisline,alsoNKG2DandDNAM1receptors
recognizeligandsonvirallyinfectedcellsthatarecommontotumorcells:MICA/BandULBPs,
andPVRandNectin2respectively.Inthiscontext,ithasbeenshownthatseveralvirusesactivate
DNAdamageresponse,acommonpathwayinvolvedintheregulationofNKG2DandDNAM1
ligandexpressionininfectedandtumorcells[53,96,97].
ViruseshavedevelopedstrategiestoevadeNKcellcontrolontheirreplicationeithertargeting
activatingorinhibitoryreceptorexpression/recognitionortamperingwiththeexpressionofcellular
ligandsforNKcellactivatingreceptorsinthecellstheyarereplicating,orsimultaneouslyinducing
combinations of these mechanisms (see table 4). Accordingly, in HIV infection NK cells are
activated[98],showdecreasedNCRexpression[99],decreasedproductionofIFNandperforin,
increasedproportionsofnoncytolyticandnonsecretingCD56CD16+ NKcells[100],increased
expression of HLAspecific inhibitory receptors (KIRs) [101], reduced expression [102], or
increasedshedding[103,104],ofligandsforactivatingreceptors.Herpesvirusesmayinteractwith
and degrade ligands for activating NK cell receptors [105107] or may encode viral proteins
mimickingHLAclassImoleculesthatwillblockNKcellfunctionthroughinteractionwithKIRs
(orNKG2A).Alongthisline,HCVmayblockNKcellfunctionthroughtriggeringofCD81onNK
cells,ormaydecreasetheirproductionofIFN uponIL12signaling[108,109],ormayinduce
theirproductionofimmunosuppressivecytokinessuchasIL10[110].
GeneticindividualvariabilityhoweverplaysarelevantroleinmoldingthegeneralizedNK/virus
interaction into different individual responses to the same invading pathogen. Inherent/genetic
carriageofgivenHLAclassIspecificinhibitoryreceptorsmayimproveNKcellactivityagainst
viruses. In HCV infection, for example, the combination of specific KIRs and HLAC alleles
associatestohigherlikelihoodtoclearacuteinfectionandtorespondtopegylatedIFNa/ribavirin
treatment.InadditionchronicallyinfectedHCVpatients displayatleasttwodifferentNKcell
transcriptionalsignatureswhichareassociatedwithdifferentresponsestoantiviraltreatment[91],
thussuggestingthatinherent/geneticNKcellregulationsaffecttheresponsetoviruses.Thisis
furtherprovenbytheobservationofdifferentNKp30orNKG2Dsurfacemodulationinpatients
clearingacuteHCVinfectionorclearingchronicinfectionuponantiviraltreatment [111114].
Similarly,inHIV1infectionanonprogressiveclinicalcourseisassociatedwithKIR3DS1and
HLABw4carriage[115]andwithaninherent/geneticregulationofNKp44,NKp30andNKp46
expressionuponNKcellactivation[116].
Overall, therefore, the manipulation of virus/NK cell interaction for the purpose of oncolytic
virotherapy may profit from addressing and generally interfering with the so far highlighted
mechanisms, but also may require additional insight in individual NK cell responses to viral
triggers.Indeedindividualgeneticandinherentpatientdifferencesmayaffecttheintendedoutcome
thusbenefitingfromintegratedindividualizedstrategies.
NKcelldependentoncolyticvectors
Forsomeoncolyticviralvectors,theantitumoreffecthasbeenreportedtolargelydependonNK
cellactivity.Forexample,theoncolyticpotentialofOrfvirusinmurinemodelsoflungcancerand
ofSindbisvirusinSCIDmicebearinghumanovariancarcinomatumorsstronglylargelydependson
NK cell activity [117118]. Increased antitumor activity of NK cells may occur due to virus
inducedmodulationoftheNKcellactivating/inhibitoryligandprofileonthesurfaceofinfected
cancercells.Indeed,infectionofgliomacells withtheoncolyticagentmyxomavirus leads to
downregulation of MHC I surface expression via the viral M153R protein and consequent
increasedNKcellmediatedlysisofhumangliomatumorsinSCIDmiceandprolongedmouse
survival [119]. Also, parvovirus infection of colon carcinoma cells leads to increased NCR
dependenttumorcellkillingbyNKcells(Bhat&Rommelaere,2013)..Besidessuchdirecteffect
onNKcellmediatedlysisoftumorcells,viralinfectionmayalsoindirectlyleadtoincreasedanti
tumor activity of NK cells. In this context, the oncolytic rhabdovirus Maraba MG1 infects
conventionaldendriticcells,whichleadstomaturationofthesecellsandconsequentlyincreased
NKcellmediatedantitumorresponses[120].
NKcellsandoncolyticvirusesincancervaccination
Somegroupshavealsoharnessedtheabilityofoncolyticvirusestotriggertheantitumorimmune
response,includingtheNKcellresponse,inthedesignofcancervaccines.Immunizationofmice
with coloncarcinomacellsthatwerepreviouslyinfectedinvitrowithanoncolyticVSVvirus
protectedtheanimalsfromsubsequenttumorchallenge,aneffectthatwasfurtherenhancedby
expressionofGMCSFbythevirus[128].Therearealsoindicationsthatthereciprocalinteraction
betweenDCandNKcellsmaybebeneficialinthecontextofcancervaccinationusingviruses.DC
loadedwithreovirusinfectedhumanmelanomacells(butnotreovirusinfectedtumorcellsalone)
inducedchemotaxisofNKcellsandIFN productionandantitumorcytotoxicityinNKcells,
whichpossiblymaycontributetotumorregression [129]. Inaddition,vaccinationofmicewith
dendritic cells (DC) harboring a nontransmissible recombinant Sendai virus prevented lung
metastasisofneuroblastoma(butnotprostaticcancer).DepletionstudiesindicatedthatNKcells
werecrucialfortheprotectiveeffect[130].
InhibitoryeffectsofNKcellsononcolyticvirotherapy
Although,asindicatedabove,(enhanced)NKcellactivitymaycontributetothetherapeuticeffects
of particular oncolytic viruses, the antiviral activity of NK cells may also lead to unwanted
prematureclearanceofthevirus,reducingitstherapeuticpotential.SuchnegativeeffectofNKcell
activity is particularly relevant when the oncolytic virotherapy involves the administration of
relativelylowdosesofvirusthatneedstoundergomultipleroundsofreplicationtosufficiently
spreadwithinthetumorandreachmaximaltherapeuticeffectiveness.Insuchcases,ideally,the
antiviraleffectofNKcellsshouldbeminimal,especiallyduringtheearlystagesoftreatment,while
retaining the antitumor activity of NK cells [131]. One approach to reach this goal is to
genetically engineer oncolytic vectors so that they display an optimized activating/inhibitory
balancetowardsNKcells,whichmayinvolvetheintroductionof(viral)NKcellevasivegenesin
theoncolyticviralgenome.
In rats bearing multifocal hepatocellular carcinoma and treated with oncolytic VSV, NK cell
depletionresultedinalogarithmicelevationofintratumoralVSVtitersandanenhancedantitumor
response,indicatingasuppressiveeffectofNKcells onthetherapeuticeffectoftheoncolytic
vectorinthissetup[132].Interestingly,geneticengineeringofherpesvirusimmuneevasiongenes
intheVSVgenomewasabletocounteractNKcellactivityandenhancetheoncolyticpotentialof
VSVinthisanimalmodel.Indeed,introductionoftheequineherpesvirus1chemokinebinding
viralgGglycoproteininVSVreducedthenumberofNKandNKTcellsinthetumors,resultingin
a1logenhancementofintratumoralvirustiters,increasedtumornecrosisandprolongedanimal
survival without toxicities [133]. In a followup study, NK cell activity was more specifically
suppressedviaintroductionofthehumancytomegalovirusUL141geneinVSV.UL141encodesa
viralproteinthatdownregulatesCD155andCD112,ligandsfortheNKcellactivatingreceptor
DNAM1[133,134].Again,recombinantVSVexpressingUL141resultedinaonelogelevationof
intratumoralvirusreplication,enhancedtumornecrosisandprolongedsurvival[135].
AnoptimizedbalanceofNKactivation/inhibitionsignalsmaybeparticularlyrelevantfor
herpessimplexvirus1(HSV1)basedoncolyticvectors,asthesetypicallydependonseveral
viralreplicationroundsandefficientspreadwithinthetumortobeeffective [136]. Indeed,
AlvarezBreckenridge et al. elegantly demonstrated that NK cells are responsible for
prematureclearanceofanHSV1basedoncolyticvectorinamouseglioblastomamodel[24].
TheyshowedthatNKcellactivityistriggeredbyHSV1inducedupregulationofNCRligands,and
that NK cellmediated clearance of the viral vector represents an important limitation in
glioblastomavirotherapy[24].Inlinewiththesedata,thepositiveeffectsofepigeneticmodulators
likevalproicacidandhistonedeacetylaseinhibitorsonHSV1basedoncotherapyinglioblastoma
mousemodelswereas foundtocorrelatewithreducedrecruitmentofNKcellstotumorbearing
brainsandsuppressedNKcellcytotoxicity [136]. Hence,itwillbeinterestingtodeterminethe
oncolyticpotentialoffuturerecombinantHSV1oncolyticvectorsthatencodeNKcellsuppressing
proteins. A particularly interesting candidate may be the gD glycoprotein of the porcine
alphaherpesviruspseudorabiesvirus(PRV),whichiscloselyrelatedtoHSV1.PRVgDhas
beenreportedrecentlytointerferewithDNAM1dependentNKcellmediatedkillingthrough
downregulationoftheDNAM1ligandCD112bothinporcineandhumancells,including
humanglioblastomacells[107].
Combinationofviro/chemotherapyandNKcells
The future of oncolytic virotherapy, like that of NK cellbased oncotherapy, will probably
involve its integration in combination therapy with more conventional approaches like
chemotherapy[84].Hence,futureresearchwillneedtocarefullyinvestigatewhethersometherapy
combinationsmayreinforceorrathercounteractoneanother.Bothtypesofoutcomehavebeen
reportedandmaydependatleastinpartonsynergisticorcounteractingeffectsonNKcellactivity
bythecombinationtherapy.Ontheonehand,inamousemodelofaggressivehumanovarian
cancer,thecombinationofSindbisvirotherapywithtopoisomeraseinhibitorchemotherapyresulted
insynergisticNKcelldependenteffectivetherapy,whichwasnotobservedwitheithertreatment
alone [137]. On the other hand, although combining oncolytic VSV with cyclophosphamide
chemotherapy increased VSV titers in mesothelioma tumors in mice, it unexpectedly reduced
therapeutic efficacy compared to cyclophosphamide alone. This antagonistic effect appeared to
involve a VSVinduced TGFdependent suppression of cyclophosphamidetriggered NK cell
activity[138].
CONCLUSIONSANDFUTUREPERSPECTIVES
Attempts at exploiting NK cell adoptive use or NK cell manipulation for a successful
immunotherapy and/or virotherapy of solid tumours (Figure 1) overall have been so far
stymied by a combination of factors including too early clearance (and inefficient tumor
penetration/intratumoralspread)ofoncolyticviruses,poorNKcellpenetrationorlocalizationin
proximityoftumorcells andsusceptibilityofinfiltratingNKcellstobemanipulatedand
disarmed.Theinformationandlessonslearntfromthesefailures,togetherwithnewinsights
gatheredinNKcellbiologyindifferenthealthconditionswillprovideanimprovedbasisfor
futureImmuno/oncovirotherapy.Inparticular,theindepthknowledgeoftheroleofNKcells
inthepresentandfuturetherapeuticapproachesisaprerequisitetoidentifycrucialsynergies
(figure1).Inthiscontext,strategiestoincreaseNKcell:tumourinteractionanddirectkilling,
andtumourtargetingdrugsormAbsarebeingpresentlyevaluated.Manipulationofviruses
usedforoncotherapywillbetargetedatreducingtooearlyvirusclearancebyNKcellsthus
allowingspereadtothewholetumorthusallowingimprovedkilling.Allthesestrategiesand
new methods will need to carefully take into account the phenotypic and functional
characteristicsofNKcellsinindividualpatients.
Finally, evidences showing that a very high NK cell phenotype diversity exists in each
individual will also need to beconsidered in future work.Indeed, standardized therapies
using NK cell manipulation in any given group of patients may conflict with different
interindividualcharacteristicsinvolvingNKcellfunctionandphenotypeinthesepatientsand
therefore may lead to treatment failure independent from an intrinsic usefulness of the
immuno/virotherapyregimen.NewtechniquesofNKcellorvirusmanipulation(e.g.single
cell transcriptional analysis, masscytomery, etc.) will provide useful tools to optimally
individualizeimmunotherapeuticregimensexploitingNKcell:tumorinteraction.
EXECUTIVESUMMARY
NKcellsandthetumormicroenvironment.
o Tumor microenvironment can regulate the availability and location of NK cells
withinthetumortissue
o TumormicroenvironmentcanregulatethefunctionofNKcellswithinthetumor
tissue
o TumorcellscanedittheirsurfacephenotypetoescapeNKcellattack
RoleofNKcellsintherapiestargetingsolidtumors
o NKbasedimmunotherapy
o mAbmediatedtumortargeting
o DrugmediatedtumortargetingandIMiDs
RoleofNKcellsinoncolyticvirotherapy
o NKcellsvirusinteraction
o NKcelldependentoncolyticvectors
o OncolyticvirotherapywithenhancedNKcellactivation
o NKcellsandoncolyticvirusesincancervaccination
o InhibitoryeffectsofNKcellsononcolyticvirotherapy
o Combinationofviro/chemotherapyandNKcells
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FIGURELEGEND.
Figure1.RoleofNKcellsintumortherapy:potentialsynergies.NKcellscanplayapivotal
role in different therapeutic strategies. In NK cellbased immunotherapies NK cells are
directlyexploitedtokilltumorcells.IntumortargetedtherapiesNKcellscanparticipateto
the antitumor therapeutic effects through different mechanisms: mAbinduced ADCC or
drugincreasedNKcellcytotoxicity.Invirotherapy,NKcellsmayexerteitherapositiveora
negativeeffectontheefficacyoftherapy.Dependingon severalfactorssuchas virus type,
virusdoseandvirusreplicationrate,NKcellscaneitherparticipateinclearingthetumorby
killinginfectedtumorcells,or limit virus spreadwithinthetumor byprematurelykilling
infectedtumorcells. Thesearchforpossiblesynergisticeffectsamongdiversetherapeutic
approaches(yellowarrows)mayrepresentavaluablestrategytothedesignoffutureeffective
therapies.
Ligand(s) on
tumor cells
Ref.
NKp46
(CD335)
Unknown
4, 6, 139
HSPGa
BAT3b/BAG6c
140
139, 141,
142
NKp30
(CD337)
B7-H6
HSPGa
NKp44
(CD336)
NKG2D
DNAM-1
(CD226)
143, 144
PCNA *
140
60
MLL5e isoform
145
HSPGa
MICA/B,
ULBP1-6
PVR (CD155)
Nectin2
(CD112)
140
53
96, 146
DNX-2401
VCN-01
ColoAd1
viral vector
human
adenovirus
expressing
GMCSF
oncolytic
adenovirus
human
adenovirus
expressing PH20
hyaluronidase
chimeric
Ad11p/Ad3
adenovirus
Indication(s)
Phase
Status
Route
Notes
Ref
Non-muscle
invasive bladder
cancer
II/III
Recruitin
g
i.ves.
as a single agent
NCT01438112
glioblastoma
glioblastoma or
gliosarcoma
solid tumors
pancreatic
cancer
Epithilial solid
tumors, bladder
and colorectal
cancer
overian
carcinoma
malignant
melanoma
Recruitin
g
Recruitin
g
Recruitin
g
Recruitin
g
i.b.p.
i.t.
i.v.
i.t.
combined with
temozolomide
combined with
IFN-
combined with
gemcitabine
combined with
gemcitabine
NCT01956734
NCT02197169
NCT02045602
NCT02045589
I/II
Recruitin
g
i.v.
as a single agent
NCT02028442
I/II
Recruitin
g
i.per.
as a single agent
NCT02028117
recruiting
e.v.
as a single agent
NCT01864759
NCT02285816
ICOVIR-5
oncolytic
adenovirus
MG1
Maraba
/MAGE-A3
rhabdo virus
expressing
tumorassociated
antigen MAGEA3
solid tumors
I/II
Recruitin
g
i.v.
Combined with
AdMa3,
adenovirus
expressing
MAGE-A3, as
priming
component
HF10
unresectable or
metastatic
melanoma
II
Recruitin
g
i.t
combined with
Ipilimumab
NCT02272855
glioma
i.t.c.
combined with
dexamethasone
NCT02031965
i.v. or i.t.
as a single agent
NCT00931931
i.pl.
as a single agent
NCT01721018
i.v.
as a single agent
NCT02192775
i.pl.
as a single agent
NCT01503177
HSV1716
Seprehvir
ICP34.5 lacking
HSV-1 mutant
non-CNS solid
tumors
malignant pleural
mesothelioma
Multiple myeloma
MV-NIS
GL-ONC1
malignant
mesothelioma
measles virus
peritoneal,
expressing
fallopian ovarian
thyroidal sodiumcarcinoma
iodide symporter
plasma cell
myeolma
attenuated
vaccinia virus
with fluorescent
reporter genes
I
I/II
II
I
Recruitin
g
Recruitin
g
Recruitin
g
Recruitin
g
Recruitin
g
II
Recruitin
g
i.per.
as a single agent
NCT02364713
I/II
Recruitin
g
i.v.
combined with
cyclophosphamid
e
NCT00450814
Recruitin
g
i.t.
as a single agent
NCT01846091
I/II
Not yet
recruiting
i.v.
combined with
cisplatin and
radiation therapy
NCT01584284
advanced solid
tumors
Recruitin
g
i.v.
as a single agent
NCT00794131
REOLYSIN
oncolytic
reovirus
combined with
FOLFIRI and
bevacizumab
combined with
paclitaxel and
carboplatin
metastatic
colorectal cancer
Recruitin
g
i.v.
non-small cell
lung cancer
II
Not yet
recruiting
i.v.
II
Recruitin
g
i.t.
as a single agent
NCT01227551
Recruitin
g
i.t.
as a single agent
NCT01628640
malignant
melanoma
primary
hepatocellular
carcinoma
NCT01274624
NTC00861627
CVA
coxsackievirus
A21
VSV-IFN
VSV virus
expressing IFN
ParvOryx
parvovirus H-1
glioblastoma
I/II
Not yet
recruiting
i.v. or i.t.
and i.t.c.
combined with
surgery
NCT01301430
NDV
new castle
disease virus
glioblastoma,
sarcoma and
neuroblastoma
I/II
Not yet
recruiting
i.v.
as a single agent
NCT01174537
Abbreviations: i.t., intratumoral; i.v., intravenous; i.per.: intraperitioneal; i.pl.: intrapleural; i.t.c.: into tumor
resection cavity; i.b.p.: in brain parychema; e.v., endvenous; i.ves.: intravesical
Influenza
virus
(IV)
Sendai virus
(SV)
Newcastle
disease virus
(NDV)
Vaccinia virus
(VV)
Dengue virus
(DV)
West Nile
virus
(WNV)
a
Activati
ng
NK
receptor
NKp46
Viral ligand(s)
on
infected cells
Ref.
HAa
(activation)
92
NKp44
93
NKp46
HA (activation)
HNb (activation)
147
NKp44
NKp46
HN (activation)
HN (activation)
93
148
NKp44
NKp30
HN (activation)
HA (inhibition)
149
NKp46
NKp44
HA (activation)
E-protein
(activation)
E-protein
(activation)
NKp44
94
94
Virus
Effect on activating
NK receptors
Herpes simplex
virus 1 (HSV-1)
Effect on ligand(s)
on infected cells
Ref.
Up-regulation of
NCR-L
(mediated by ICP0
protein)
150
24
Down-regulation of
NKp30-L and NKp46L
Up-regulation of
NKp46, NKp30, NKp44
on maturing NK cells
Herpes simplex
virus 2 (HSV-2),
Pseudorabies
virus
(PRV)
Cytomegalovir
us
(CMV)
151
Down-regulation of
NKG2D-L
152
Degradation of
Nectin2 (mediated
by gD)
107
Modulation of NKp30
function
(mediated by
pp65/UL83)
153
Down-regulation of
NKp46-L and NKp30L
154
105
Kaposis
sarcomaassociated
herpesvirus
(KHSV)
Human
herpesvirus 8
(HHV8)
Vaccinia virus
Hepatitis C
virus
(HCV)
Modulation of
NKG2D-L (mediated
by UL16, UL141,
UL142, miR-UL112)
Down-regulation of
NKp44-L (mediated
by ORF54/dUTPase)
Down-regulation of
NKp46, NKp30,
NKG2D
Up-regulation of
NKp46 and NKp30
155
Up-regulation of
NKG2D-L
156
Up-regulation of
NCR-L
95,
149
110
Down-regulation of
NKp30
91,,
157
Transient induction of
NKp30 and NKG2D
(acute infection and
111,
112
exposed-uninfected
pts)
Parvovirus
HIV-1
Up-regulation of
NCR-L
Down-regulation of
NCR
158
99
Up-regulation of
NKp44-L (mediated
by gp41S3peptide)
159
Intracellular
retention of NKp44-L
(mediated by nef)
160
Down-regulation of
NCR-L
102
Up-regulation of
NKG2D-L (mediated
by vpr)
102,
161
103
Shedding of NKG2DL
Expansion of CD56CD16+NCR- subset
Myxoma Virus
(MYXV)
HCMV
Chikungunya
virus
Hantavirus
Expansion of NKG2C+
subset
Expansion of NKG2C+
subset
Expansion of NKG2C+
subset
Down-regulation of
NKG2D-L (mediated
by nef)
Down-regulation of
Nectin-2
104
100
119
162
90
163