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ORIGINALRESEARCH
published:15June2021
doi:.682658
TreatmentInducedCytotoxic
T-CellModulationinMultiple
MyelomaPatients
GregorioBarilà,LauraPavan,SusannaVedovato,TamaraBerno,MariellaLoSchirico,
MassimilianoArangioFebbo,AntonellaTeramo,GiuliaCalabretto,CristinaVicenzetto,
VanessaRebeccaGasparini,AnnaFregnani,SabrinaManni,ValentinaTrimarco,
SamuelaCarraro,MonicaFacco,FrancescoPiazza,GianpietroSemenzato
andRenatoZambello*
DepartmentofMedicine(DIMED),HematologyandClinicalImmunologySection,PaduaUniversitySchoolofMedicine,
Editedby:Padova,Italy
RobertoMina,
UniversitàdegliStudidiTorino,Italy
Reviewedby:Thebiologyofplasmacelldyscrasias(PCD)involvesbothgeneticandimmune-related
MattiaD’Agostino,(MM)
UniversityofTurin,Italyevolution,severalauthorshypothesizedthatimmunedysfunctioninvolvingbothBandT
MicheleCea,
UniversityofGenoa,
*Correspondence:istoevaluatetheimpactofcornerstonetreatmentsforMultipleMyelomaintoimmune
r.******@
Specialtysection:samplesdisplayedareductionofCD4+cells(p<)andanincreaseofCD8+
Thisarticlewassubmittedto(p<),CD8+/DR+(p<)andCD3+/CD57+(p<)
HematologicMalignancies,findingsweretosomeextentdemonstratedalsofollowingbortezomibtreatment,amore
asectionofthejournal
FrontiersinOncologypronouncedcytotoxicpolarizationwasshownafterexposuretoautologousstemcell
Received:18March2021transplantation(ASCT)andLenalidomide(Len),samplesof
Accepted:10May2021patientswhoreceivedASCT(n=110)andLen(n=118)werecharacterized,towards
Published:15June2021
untreatedpatients(n=138andn=130,respectively),byhigherlevelsofCD8+(p<
Citation:
BarilàG,PavanL,VedovatoS,andp<,respectively),CD8+/DR+(p==,respectively)and
BernoT,LoSchiricoM,CD3+/CD57+cells(p<=,respectively)andlowerlevelsofCD4+
ArangioFebboM,TeramoA,lymphocytes(p<=,respectively).WedemonstratedthatactiveMM
CalabrettoG,VicenzettoC,
GaspariniVR,FregnaniA,patientsarecharacterizedbyarelevantTcellmodulationandthatmostofthesechanges
ManniS,TrimarcoV,CarraroS,aretherapy-,notablyASCTandLentreatments,
FaccoM,PiazzaF,SemenzatoG
andZambelloR(2021)Treatmentpolarizeimmunesystemtowardsadominantcytotoxicresponse,likelycontributingtothe
InducedCytotoxicT-CellModulationanti-Myelomaeffectoftheseregimens.
inMultipleMyelomaPatients.
::multiplemyeloma,immunophenotyping,treatment,lenalidomide,ASCT-autologousstemcell
doi:.682658transplantation,cytotoxicresponse
FrontiersinOncology||Volume11|Article682658:.
Barilà
INTRODUCTIONMyelomaandactiveMultipleMyelomafollowedatthe
HematologyUnitofPaduaUniversityHospitalwasstudied.
Thebiologyofplasmacelldyscrasias(PCD)involvesbothgeneticBonemarrowsampleswerecollectedfromOctober2012to
andimmune-relatedfactors(1).ThepathogenesisofMultipleNovember2019atdifferenttimepointsaccordingtoclinical
Myeloma(MM)isamulti-stepprocessinwhichprimaryeventspractice,toconfirmcompleteresponseorincaseofprogressive
,
anddevelopmentofapre-neoplasticconditiondefinedasMGUS,WaldenströmMacroglobulinemia,lightchain
monoclonalgammopathyofundeterminedsignificance(MGUS).amyloidosis,light/heavychaindepositiondiseaseandPOEMS
Theacquisitionofsecondaryadditionaleventssetsthetransitiontosyndromewereexcludedfromthestudy.
anovertneoplasticandinitiallyasymptomaticconditionThisstudywasconductedaccordingtotheguidelinesofthe
(smolderingMultipleMyeloma,SMM)andthentoanactiveDeclarationofHelsinki,andapprovedbytheInstitutional
MM(AMM)requiringtreatment(2–4).However,whole-exomeReviewBoardofAziendaOspedalieradiPadova(2491P,
sequencingstudiesofpairedsamplesfromMGUS,SMMandPD-MM-REG1).Allpatientsgavewritteninformedconsensus
AMMpatientsdemonstratedthatmostsomaticmutationspriortoinclusioninthestudy.
precededthediagnosisofMM,suggestingthatgeneticlesionsare
necessarybutnotsufficientfortheevolutionfromapre-neoplasticFlowCytometryAnalysis
conditiontoanovertneoplasticdisease(5,6).Consequently,Flowcytometryanalysiswasperformedonfreshbonemarrow
microenvironmentandmorespecificallyanimmunedysfunctionbyflowcytometryanalysisusingdirectorindirect
alsoplaysakeyroleinMMpathogenesis,,
systemimpairmentcontributestotheprogressionofthedisease(7,cellswerestainedwiththeappropriatemAbs,scoredusinga
8).QuantitativeandfunctionalalterationsinvolvingNaturalKillerFACSCantoanalyzer(BDBiosciences,SanJoseCA)anddata
cells(NKcells),BandTlymphocytesarewellknownanddescribedprocessedbytheBDFACSDivasoftwareprogram(BD
inpreviousstudies(8–10).Biosciences).Bonemarrowlymphocyteswerestainedwith
AsfarastheBcellcounterpartisconcerned,immune-paresisfluorochromeconjugatedantibodiesforCD4(FITC,clone
isawell-knownriskfactorofprogressionfromSMMtoAMMSK3),CD8(PE,cloneSK1),HLA-DR(PerCP,cloneL243),
(11)andsecondaryhypogammaglobulinemiacontributestoCD5(PeCy7,cloneL17F12),CD19(APC,cloneSJ25C1),
infectiveeventsthatrepresentacommonclinicalfeatureintheCD57(FITC,cloneHNK-1),TCRgd(PE,clone11F2),CD16
settingofsymptomaticMMgettingworsepatients’survival(12,(PerCP-,clone3G8),CD56(PeCy7,),
13).NKcellsarefunctionallyandphenotypicallyalteredinPCDCD3(APC,cloneSK7)andCD45(APC-Cy7,clone2D1)(BD
andprogressionofMGUStoMMischaracterizedbyreductionofBiosciences).Basedonthesecombinations,thefollowingsubsets
cytotoxicpropertiesandacquisitionofan“exhausted”phenotypeoflymphocyteswereidentified:CD3+T,CD4+Tcells,CD8+T
(14,15).AlsotheimpairmentofTcellcompartmentsinvolvingcells,CD8+/DR+Tcells,CD3+/CD57+TcellsandCD3+/Tgd+
bothCD4+andCD8+lymphocytescontributestoMyelomacells,CD19+BlymphocytesandCD19+/CD5+Bcells,CD3-/
pathogenesiswithprogressivereductionincytotoxicpropertiesCD16+/CD56+NKcellsalongwiththeCD3-/CD16+/CD56+/
andacquisitionofanexhaustedoranergicstate(7,8,16,17).CD57+NKcellsubset.
Despitedifferentstudieshavebeenfocusedonthecharacteristic
ofimmunecellsofpatientswithPCD,mostofthemincludedStatisticalAnalysis
limitedsmallcohortsofselectedpatientsenrolledinclinicaltrialDataareexpressedasmeanplusorminusthestandarddeviation
(17–21).Moreover,inmoststudiesonlyperipheralbloodsamples(SD),andstatisticalanalysiswasperformedbyt-testorbyone-
havebeenanalyzed(19,20,22),thusrulingtheevaluationoutofwayAnovafollowedbyTukey’smultiplecomparisontest,when
,-value<.
samplesofalargecohortof735patientsaffectedbyPCDwere
aimofthisstudyistoevaluatetheimpactofcornerstone
treatmentsforMultipleMyeloma,namelyautologousstemcellRESULTS
transplantation(ASCT)andnovelagentslikebortezomibandDistributionofImmuneSubsetsinPlasma
lenalidomide,
976consecutivebonemarrowsamplesof746patients’samples
MATERIALSANDMETHODScollectedfromOctober2012toNovember2019weredistributed
asfollows:167samplesfrom164MGUSpatients,224samples
StudyPopulationfrom206SMMpatientsand585samplesfrom376AMM
,254werefromnewly
patientsaffectedbyPCDincludingMGUS,smolderingMultiplediagnosedpatients(NDMM),whiletheremnant331belongedto
FrontiersinOncology||Volume11|Article682658:.
Barilà
TABLE1|Clinicalfeaturesofthestudycohort.
MGUS(n=167)sMM(n=224)nMM(n=254)tMM(n=331)
MedianAge(years)62(24-93)67(35-85)69(39-90)65(38-87)
Sex
Female73/167(%)96/224(%)118/254(%)156/331(%)
Male94/167(%)128/224(%)136/254(%)175/331(%)
Isotype
IgG112/167(%)144/224(%)152/254(%)211/331(%)
IgA36/167(%)57/224(%)49/254(%)44/331(%)
IgD0/1670/2244/254(%)6/331(%)
Lightchain8/167(%)13/224(%)42/254(%)47/331(%)
Byphenotypical11/167(%)10/224(%)3/254(%)6/331(%)
Non-secretory0/1670/2244/254(%)17/331(%)
MGUS,Monoclonalgammopathyofundeterminedsignificance;sMM,smoulderingMultipleMyeloma;nMM,newlydiagnosedMultipleMyeloma;tMM,treatedMultipleMyeloma.
treatedpatients(TMM);indetailn=192(%)±%,p<,±%±%,p=
AutologousStemCellTransplantation(ASCT),n=300(%)±%±%,p=,respectively,Supplementary
bortezomib(Bort)treatmentandn=118(%)lenalidomideFigure1C).ConsideringtotalNKcellsandCD57+NKcells,no
(Len)treatment(Table2).BonemarrowsamplesoftreatedsignificantdifferenceswerefoundinTMMpatientsascompared
patientswereperformedaccordingtoclinicalpractice,totoNDMM,SMMandMGUSpatients(NKcells:±%vs
±,p=,±%±%,p=
Consideringtotalbonemarrowlymphocytes,±%±%,p=,respectively,
displayedreducedlymphocytespercentagestowardsNDMMSupplementaryFigure1D;CD57+NKcells:±%±
samples(±%±%,p=);%,p=,±%±%,p=±%vs
±%,p=,SupplementaryFigure1E).
TMMcases,nosignificantdifferenceswerefoundintotalTcellsAnalysisofTcellsubsetsshowedthatTMMcaseswere
percentagesascomparedtoNDMM,SMMandMGUSpatientscharacterized,withrespecttoNDMM,SMMandMGUS
(±%±%,p=,±%±samples,bylowerCD4+lymphocytespercentages(±
%,p=±%±%,p=,±,p<,±%±%,p<
respectively,Figure1A).±%±%respectively,p<,Figure
showsignificantdifferencesintotalBlymphocyteslevelswith1B)andhigherCD8+(±%±%,p<,
respecttoNDMM,SMMandMGUSsamples(±%±%±%,p<±%±
±%,p=,±%±%,p=%respectively,p<,Figure1C),CD8+/DR+(±
±%±%,p=,%±%,p<,±%±%,
1A)asignificantreductioninCD19+/CD5-Bcellstowardsp<±%±,p<,
MGUS(±%±%,p=,SupplementaryFigure1D)andCD3+/CD57+cellslevels(±%±
Figure1B)andasignificantincreaseinCD19+/CD5+%,p<,±%±%,p<±
comparedtoNDMM,SMMandMGUSwasfound(±%%±%,respectively,p<,Figure1E),whileno
significantdifferenceswerefoundinTgdlevels(Figure1F).
TABLE2|ClinicalfeaturesoftreatedMMpatients.
TreatmentRelatedEffectsonImmune
TreatedMM(n=331)SystemCellsinMMPatients
N°ofprevioustreatmentOurresultsdemonstratedthatMyelomatreatmentinducesan
1201/331(%)
275/331(%)evidentinrelationshiptothenumberofpreviouslinesof
≥355/331(%),excludingsamplesofpatientsinwhombone
Typeofprevioustreatment
Bortezomib300/331(%)marrowwasperformedwithin3monthsfromASCT(n=83),in
Bortezomibalone*77/331(%)patientswhoreceived>1lineoftreatmentamorepronounced
Lenalidomide118/331(35
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