INTRODUCTION

Despitetremendousimprovementsintreatmentstrategiesagainstepithelialovariancancer,epithelialovariancancer

isstill themost lethaltumoramonggynecologicmalignan-cies,andisthefourthmostcommoncauseofcancer-relateddeathsamongwomenworldwide.Althoughovariancancerhasnotbeentraditionallyconsid-

eredtoberesponsivetoimmunotherapy,thereis increasingevidencethat indicatesovariancancersare immunogenic.Thisevidence isderived fromnumerousclinical findingsshowingspontaneousantitumor immuneresponses [1-4],tumor immuneevasionmechanisms [5-7],andclinical re-sponsesto immunotherapy [8-13] inpatientswithovarian

Original Article

Overexpression of CD73 in epithelial ovarian carcinoma is associated with better prognosis, lower stage, better differentiation and lower regulatory T cell infiltrationHoon Kyu Oh1, Jeong-Im Sin2, Junghae Choi3, Sung Hae Park4, Tae Sung Lee4, Youn Seok Choi4

1Department of Pathology, Catholic University of Daegu School of Medicine, Daegu; 2Department of Microbiology, Kangwon National University School of Medicine, Chuncheon; 3Department of Molecular Biology, College of Pharmacy and Life & Nanopharmaceutical Science, Kyung Hee University, Seoul; 4Department of Obstetrics and Gynecology, Catholic University of Daegu School of Medicine, Daegu, Korea

Received Apr 3, 2012, Revised Apr 28, 2012, Accepted May 12, 2012

Correspondence to Youn Seok ChoiDepartment of Obstetrics and Gynecology, Catholic University of Daegu School of Medicine, 33 Duryugongwon-ro 17-gil, Nam-gu, Daegu 705-718, Korea. Tel: 82-53-650-4087, Fax: 82-53-650-4078, E-mail: drcys@cu.ac.kr

pISSN 2005-0380 eISSN 2005-0399

Copyright © 2012. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Objective:ThepurposeofthecurrentstudywastoevaluatesurvivaloutcomeaccordingtotheexpressionstatusofCD73inpatientswithepithelialovariancancer.Methods:A totalof167patientswithepithelialovariancancerwereenrolled in thecurrentstudy.Foreachpatient,aretrospectivereviewofmedicalrecordswasconducted. ImmunohistochemicalstainingforCD73,CD8,FoxP3,andCD68wasperformedusingtissuemicroarraymadewithparaffinembeddedtissueblock.Results:Amongtheenrolledpatients,29.9%ofpatients (n=50)showednegativeexpressionforCD73,whereas70.1%ofpatients(n=117)showedpositiveexpressionforCD73.TheCD73positivegroupshowedbetterprognosiscomparedtotheCD73negativegroup(5-yearoverallsurvivalofCD73positivegroup,73.0%;thatofCD73negativegroup,50.1%;p=0.023).CD73wasmorefrequentlyexpressedinmucinousadenocarcinomaandclearcellcarcinomacomparedtoserousorendometrioidadenocarcinoma.Inaddition,CD73overexpressionsweremorefrequentlydetectedinpatientswithknowngoodprognosticfactors, i.e., lowstage,well/moderatedifferentiation,negativeperitonealcytology,nolymphovascular involvement,andnomacroscopicresidualtumorafterdebulkingsurgery.TherewassignificantlymoreinfiltrationofregulatoryTcells intheCD73negativegroupcomparedtotheCD73positivegroup.Conclusion:Goodprognosis inpatientswithoverexpressionofCD73maybeduetothatoverexpressionofCD73wasmorefrequentlyobservedinepithelialovariancancerpatientswithknowngoodprognosticfactors.Therefore,thisresultmeansthatfavorabledifferentiationandstagehavemoreinfluenceonsurvivaloutcomethanadverseeffectofCD73perse.

Keywords:Carcinoma,CD73,Ecto-5’-nucleotidase,Ovarianneoplasms,Survival

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cancer,highlightingthatimmunotherapymaybeapplicabletotreatingovariancancer.Althoughtherehavebeensuccessfulreportsofcancerimmu-

notherapyinanimalstudies,clinicalfindingsaredisappointingwithlittleimprovementofsurvivaloutcomeinpatients.Ithasbeenreportedthatinefficienttumorrejectionisnotonlythepassiveresultofinsufficienteffectorcells[14],butthattumorsalsoactivelyfightbackbyutilizingimmune-suppressivemech-anismsthatprotectthemfromeradication[14,15].CD73,alsoknownasecto-5’-nucleotidase (ecto-5’-NT)or

5' -nucleotidase (5’-NT), isaglycosyl-phosphatidylinositol-linked70-kDacell surfaceenzymethat isencodedby theNT5Egene.Normally,CD73isexpressedonendothelialcellsandsubsetsofhematopoieticcells.CD73wasoriginallyde-finedasalymphocytedifferentiationantigen. It likelyactsasacosignalingmoleculeonTlymphocytes,andisimportantasanadhesionmoleculefor lymphocytebindingtotheendo-thelium[16,17].CD73catalyzesthedephosphorylationofad-enosinemonophosphate(AMP)andothernucleosidemono-phosphates[17].Consequently,adenosineisaccumulatedininterstitialfluidfromthedephosphorylationofAMP.Extracel-lularadenosineinhibitsTlymphocyteactivationandeffectorfunctionbysignalingprimarilythroughA2aandA3adenosinereceptorsonthesurfaceofTcells.A2aadenosinereceptorsignalinghasalsobeenimplicatedintheinhibitionofcyto-kineproductionandcytotoxicactivitybynaturalkillercells[18].CD73iswidelyexpressedonmanytumorcelllinesandisupregulatedincanceroustissuesincludingthoseofthecolon,lung,pancreas,andovary.CD73isalsoassociatedwithdrugresistance,tumorcellsproliferation,tumorneovascularization,invasiveness,andmetastasisofcancercells[19,20].ThesedatasuggestthatCD73expressedontumorcellsmightfunctionasthenegativeregulatoroftumorcontrolimmunologically.Consideringtheabove-mentionedfunctionsofCD73,pa-

tientswithcancercellsexpressingmoreCD73arelikelyhavepoorsurvivaloutcome.However,onlysparse informationisavailableregardingthesurvival influenceofCD73expressionontumorcells inpatientswithmalignancies.Therefore,thepurposeof thecurrentstudywastoevaluatesurvivalout-comeaccordingtotheexpressionstatusofCD73inpatientswithepithelialovariancancer.

MATERIALS AND METHODS

1. Enrolled patientsWesearched forpatientswithepithelialovariancancer

whounderwentstagingoperationswithorwithoutadjuvantchemotherapy inourdepartment inanoncologydatabase

maintainedatourdepartment. Inclusioncriteriawereasfol-lows:1)patientswithepithelialovariancancer(queryterm;serous,mucinous,clear,endometrioid,transitional,malignantBrenner);2)patientswhounderwentprimarytherapyinourdepartment;and3)patientsdiagnosedbetweenJanuary2000andDecember2010.ThisretrospectivestudywasapprovedbytheInstitutionalReviewBoardofDaeguCatholicUniversityMedicalCenter.Applyingtheinclusioncriteria,atotalof167patientswith

epithelialovariancancerwereenrolledinthecurrentstudy.Foreachpatient,aretrospectivereviewofmedical recordswasconducted.Thehistologicslidesofthesurgicallyremovedovariancancertissueswerereviewedagainby1pathologist(HKO),whowasblindedtotheclinicalvariablesofthepatient.

2. Definitions of overall survival and disease-free survivalOverallsurvival(OS)wasdefinedasthetimefromthedate

ofdiagnosistodeathfromepithelialovariancancer.Patientswhosurvivedbeyondthetimeofanalysiswerecensoredatthetimeoftheirlastfollow-update.Disease-freesurvival(DFS)wasdefinedasthetimefromdateofdiagnosistotherecur-renceofcancerinanysites.

3. Construction of tissue microarrays (TMA)Representativeparaffintumorblockswereselectedaccord-

ingtotheprimaryevaluationofH&EstainedslidesofovariancancerbeforetheywerepreparedforTMA.Twotumortissuecores(1mmindiameter)weretakenfromeachofthedonorovariancancer tissueblockswithamanualpuncharrayer(Quick-Ray,Uni-TechScience,Seoul,Korea).Thecoreswereplacedinanewrecipientparaffinblockthatultimatelycon-tained59to91tissuecores.Eacharrayblockcontainedbothtumorandcontroltissue(lung,breast,andprostatecancertis-suesandnormalbreast,colon,endometrium,ovary,andtonsiltissues)samples.Multiplesections(5µminthickness)werecutfromtheTMAblocksandthenmountedontomicroscopeslides.TheTMAH&Estainedsectionswerereviewedunderlightmicroscopytoconfirmthepresenceofrepresentativetumorareas.

4. Immunohistochemical stainingImmunohistochemistrywasconductedon5µmthickTMA

tissuesectionsusingtheBondPolymer IntenseDetectionSystem(LeicaMicrosystems,MountWaverley,VIC,Australia)accordingtothemanufacturer’sinstructionwithminormodi-fications.Briefly,the5-µmthicksectionsofformalinfixedandparaffinembeddedTMAtissuesweredeparaffinizedwithBondDewaxSolution(LeicaMicrosystems),andanantigenre-trievalprocedurewasperformedusingBondERSolution(Leica

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Microsystems)for30minutesat100oC.Theendogenousper-oxidasewasquenchedfollowing5-minute incubationwithhydrogenperoxide.Sectionswereincubatedfor15minutesatambienttemperaturewithamousemonoclonalanti-CD73antibody (ab91086,1:100;Abcam,Cambridge,MA,USA),amousemonoclonalanti-FOX-P3 (ab20034,1:50;Abcam),amousemonoclonalanti-CD8antibody(m7103,1:200;DAKO,Glostrup,Denmark),andamousemonoclonalanti-CD68an-tibody(M0876,1:200;DAKO),usingabiotin-freepolymerichorseradishperoxidase-linkerantibodyconjugatesysteminaBond-Maxautomaticslidestainer(LeicaMicrosystems).Humantonsil (CD8,CD68,andFOX-P3),andlungcarcinoma(CD73)tissueswereusedaspositivecontrols.

5. Interpretation of immunohistochemical stainCD73expression levelsweregradedonascaleof0 to3

basedoncytoplasmicandmembranestainingintensityandtheproportionofpositivetumorcellsbyanexpertpathologistwhowasblindedtothepatient’sclinicalrecords.Thestainingwasgradedas0ifnocancercellswerereactive,1ifstainingwasweaklypositivein<1/3ofcancercells,2 ifstainingwasweaklypositivein>2/3ofcancercells,orstronglypositivein>1/3ofcancercells,and3ifstainingwasweaklypositiveinmostcancercells,orstronglypositivein>2/3ofcancercells(Fig.1). ImmunohistochemicalstainingforCD73 inovariancancertissuewasclassifiedasnegative(grade0)orpositive(grade1 to3).FOX-P3nuclearexpressionwascountedas

Fig. 1. Representatives of CD73 expression of each grade in immunohistochemical staining (x200). The staining was graded as 0 if no cancer cells were reactive, 1 if staining was weakly positive in <1/3 of cancer cells, 2 if staining was weakly positive in >2/3 of cancer cells, or strongly positive in >1/3 of cancer cells, and 3 if staining was weakly positive in most cancer cells, or strongly positive in >2/3 of cancer cells. Normally, endothelial cells and some of lymphocytes express CD73.

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positivemononuclearcells in3highpowerfields(×400) ineachtumorcore.CD8andCD68cytoplasmicandmembraneexpressionlevelsweregradedonascaleof0to3basedon

theproportionofpositivemononuclearcellsinfiltratedintheintratumoralandperitumoralstromaltissue.Arbitrarycutoffpointsat1%(grade0),5%(grade1),25%(grade2),and50%(grade3) foreachpositivecellper infiltrated immunecellswereused.

6. Statistical analysisComparisonsofvariablesbetweenthegroupswerebased

onthechi-squaretestand independentt-test.TheOSandDFSwereestimatedbythelife-tablemethodofKaplan-Meier.Differencesinsurvivalrateswereassessedbythelog-ranktest.Thep-valuesweretheresultoftwo-sidedtestsandp<0.05wasconsideredstatisticallysignificant.MultivariateanalysiswasperformedbyCoxregressionhazardmodel.StatisticalanalysiswasdoneusingSPSSver.13(SPSSInc.,Chicago, IL,USA).

RESULTS

Characteristicsofenrolledpatientsareshown inTable1.Briefly,meanagewas50.3years,andthemeanofthelargesttumordiameterobtainedfromthe imagingstudy(ultraso-nography,computedtomographyormagnetic resonanceimaging)was11.6cm.ThenumberofpatientsineachFIGOstagewasasfollows;stageIA39,IB4,IC18,IIA2,IIB9,IIC13,IIIA2, IIIB9, IIIC60,and IV11. Intermsofpathologictypes,serousadenocarcinomaaccountfor43.7%,mucinousadeno-carcinoma24.0%,endometrioidadenocarcinoma18.6%,clearcellcarcinoma12.6%,andtransitionalcellcarcinoma1.2%,respectively.TheexpressionstatusofCD73 in immunohistochemical

stainingisshowninTable2.Atotalof29.9%(n=50)patientsshowednegativeexpression,andtheotherpatients(70.1%)showedpositiveexpression(fromgrade1tograde3).SurvivalanalysiswasconductedaccordingtoCD73expressionstatus.

Table 1. Characteristics of the patients enrolled in this study (n=167)

Characteristic Value

Age (yr) 50.3±13.5 (15-77)

Parity 2.4±1.6 (0-8)

Largest tumor diameter (cm) 11.6±6.5 (1-34)

CA-125 649.9±1,075.4 (2.9-5,000)

CA 19-9 122.2±390.8 (0.5-3,238)

Lactate dehydrogenase 512.9±355.7 (150-3,112)

Stage

Stage I 61 (36.5)

IA 39

IB 4

IC 18

Stage II 24 (14.4)

IIA 2

IIB 9

IIC 13

Stage III 71 (42.5)

IIIA 2

IIIB 9

IIIC 60

Stage IV 11 (6.6)

Pathologic type

Serous adenocarcinoma 73 (43.7)

Mucinous adenocarcinoma 40 (24.0)

Endometrioid adenocarcinoma 31 (18.6)

Clear cell carcinoma 21 (12.6)

Transitional cell carcinoma 2 (1.2)

Differentiation

Well differentiated 48 (28.7)

Moderate differentiated 37 (22.2)

Poorly differentiated 82 (49.1)

Cytology

Negative 113 (67.7)

Positive 54 (32.3)

Ascites

Absent 69 (41.3)

Present 98 (58.7)

Lymphovascular involvement

Absent 101 (60.5)

Present 66 (39.5)

Values are presented as mean±SD (range) or number (%).

Table 2. Immunohistochemical (IHC) staining for CD73

Grade of IHC No. of patients (%)

Negative 0 50 (29.9)

Positive +1 72 (43.1)

+2 29 (17.4)

+3 16 (9.6)

The staining was scored as 0 if no cancer cells were reactive, 1 if staining was weakly positive in <1/3 of cancer cells, 2 if staining was weakly positive in >2/3 of cancells, or strongly positive in >1/3 of cancer cells, and 3 if staining was weakly positive in most of cancells, or strongly positive in >2/3 of cancer cells.

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BecauseallpatientswithpositiveCD73expressionshowedsimilarsurvivaloutcome(5-yearOSestimationofgrade1,72.5%;grade2,77.9%;andgrade3,66.7%,respectively;p=0.760),thepatientsweregroupedasCD73positiveandCD73negativegroupsforfurtheranalysis.Contrary toourexpectations, theCD73positivegroup

showedbetterprognosiscomparedto theCD73negativegroup(5-yearOS:CD73positivegroup,73.0%;CD73nega-tivegroup,50.1%;p=0.023;5-yearDFS:CD73positivegroup,53.4%;CD73negativegroup,24.1%;p=0.021)(Fig.2).BecausethereweremorepatientswithmucinousadenocarcinomaintheCD73positivegroup,weconductedasubanalysisforpatientswithnon-mucinousadenocarcinoma.Inasubgroupanalysis forpatientswithnon-mucinousepithelialovariancancer,althoughthedifferencedidnot reachtostatisticalsignificance,theCD73positivegroupshowedatendencytohavebetteroverallsurvivalthantheCD73negativegroup(5-yearOSofthenon-mucinousCD73positive[n=81]andnega-tive[n=46]groupwas69.4%and47.4%,respectively;p=0.052,Logranktest).WecomparedthefrequenciesofCD73overexpression(posi-

tiveexpression, fromgrade1tograde3)accordingtoclini-copathologicvariables.CD73wasmorefrequentlyexpressedinmucinousadenocarcinomaandclearcellcarcinomacom-paredtoserousorendometrioidadenocarcinoma. Inaddi-tion,CD73overexpressionsweremorefrequentlydetectedinpatientswithknowngoodprognosticfactors, i.e., lowstage,well/moderatedifferentiation,negativeperitonealcytology,nolymphovascularinvolvement,andnomacroscopicresidualtumorafterdebulkingsurgery(Table3).ToevaluatetheassociationofCD73expressionwithimmune

celldeposition,wecomparedthedifferencesinthedegreesornumbersof immunecelldepositionsaccordingtoCD73expressionstatus.TherewerenodifferencesinthedepositionsofcytotoxicTlymphocyte(CD8positivecells)andmonocyte/macrophage(CD68positivecells)betweentheCD73positiveandCD73negativegroup.However,thereweresignificantlymoreTreg(regulatoryTcell,FOX-P3positivecells)intheCD73negativegroupcomparedtotheCD73positivegroup(Table4).MultivariateanalysisusingCox regressionhazardmodel

showedthatage,stage,optimaldebulkingsurgery,differen-tiation,andtumorsizewereindependentprognosticfactors,butCD73overexpressionwasnot(Table5).

Table 3. The frequencies of CD73 overexpression according to clinicopathologic variables

Clinicopathologic variable No. of patients

CD73 over-expression (%) p-value*

Histologic type 0.001

Serous adenocarcinoma 73 41 (56.2)

Mucinous adenocarcinoma 40 36 (90.0)

Endometrioid adenocarcinoma 31 20 (64.5)

Clear cell carcinoma 21 18 (85.7)

Transitional cell carcinoma 2 2 (100)

Stage 0.001

I 61 54 (88.5)

II 24 14 (58.3)

III 71 43 (60.6)

IV 11 6 (54.5)

Grade 0.001

Well differentiation 48 41 (85.4)

Moderate differentiation 37 30 (81.1)

Poorly differentiation 82 46 (56.1)

Cytology 0.035

Negative 113 85 (75.2)

Positive 54 32 (59.3)

Ascites 0.052

Absent 69 54 (78.3)

Present 98 63 (64.3)

Lymphovascular involvement 0.012

Negative 101 78 (77.2)

Positive 66 39 (59.1)

Maximal size of residual tumor (cm) 0.021

No macroscopic 90 72 (80.0)

<1 28 17 (60.7)

<2 28 15 (53.6)

≥2 21 13 (61.9)

*Chi-square test.

Fig. 2. Survival analysis according to the expression status of CD73. Five year overall survival of CD73 positive (n=117) and negative (n=50) group was 73.0% and 50.1%, respectively (p=0.023, Log rank test).

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DISCUSSION

Inthisstudy,weobservedthatCD73overexpressionwasmorefrequentlyobservedinepithelialovariancancerpatientswithknowngoodprognosticfactors, includinglowerstage,well/moderatedifferentiation,negativeperitonealcytology,nolymphovascularinvolvement,andnomacroscopicresidualtumor.TheseresultedinpatientsshowingCD73overexpres-sionhadbettersurvivaloutcomecomparedtothosewithoutCD73expression.However,CD73overexpressionwasnotindependentprognosticfactor inmultivariateanalysisusingCoxregressionhazardmodel.ThesefindingswereunexpectedbecauseCD73expressedin

tumortissuehasbeenreportedtobedetrimentaltoimmuno-logiccontroloftumorinanimalstudies,andhasbeenshowntobeassociatedwith tumorproliferation,metastasis,andinvasion[19-21].Previousstudiesshowedthatelevatedlevelsofadenosineinsolidtumorsresultinimpairedkillingoftumorcellsbyimmuneeffectorcellsviamultipleimmuneresponses,suchasinhibitionofcytotoxicandhelperTlymphocytefunc-tion, inhibitionoftheadhesionofcytotoxicTlymphocytetocancercells,andinhibitionofnaturalkillercellfunction[18,19].Onepossibleexplanation for theunexpectedbetterout-

comeintheCD73positivegroup is thatoverexpressionofCD73wasmore frequentlyobserved inwell/moderatedif-

ferentiatedcarcinomacellsinthisstudy.Itiswellknownthatawelldifferentiatedcancercelltypeisassociatedwithlowerstage.Lowerstageresultsinmoreoptimalsurgeryandbetterprognosis.Therefore,theresultofourstudymeansthatfavor-abledifferentiationandstagehavemoreinfluenceonsurvivaloutcomethantheadverseeffectofCD73perseonthehost’slocalimmunesystem.OurfindingsaresupportedbythoseofRackleyetal. [22].

Rackley’sgroupreportedthatCD73(5’-nucleotidase)activitywaslowerinprostaticcarcinomasthaninbenignprostatichy-perplasia[22].TheyshowedthattheCD73activityofprostaticcarcinomacorrelateswellwiththedegreeofhistologicaldif-ferentiation;thatis,thetissueextractsofpoorlydifferentiatedcarcinomascontainlowerlevelsofCD73[22].OurfindingthatnegativeexpressionofCD73wasassociatedwithpoorlydif-ferentiatedcarcinomaisinthesamelinewiththatofRackleyetal. [22].Thus, itcanbespeculatedthatwelldifferentiatedcancercellstendtoproducemorenormalproteinsincludingCD73thanpoorlydifferentiatedcancercells.AssociationofTcellinfiltrationinovariancancertissueswith

survivaloutcomeisawellknownphenomenon[1-5,23].Inourstudy,however,therewasnosignificantdifferenceinCD8+Tcells infiltration levelsbetweenCD73positiveandnegativepatients. Instead,regulatoryTcellswerefoundless inCD73positivepatientsshowingbetterprognosis,ascomparedtoCD73negativepatients.Thisdataisconsistentwiththedataofothergroupsintheaspectthatpatientshavinglowerregu-latoryTcells infiltrationhavebetterprognosis[5].However,consideringthatCD73ontumorcellsadverselyaffect the

Table 4. Comparison of immune cells deposition in ovarian cancer tissue between the patients with CD73 negative and CD73 positive expression

Variable CD73 negative (n=50)

CD73 positive (n=117) p-value

CD8+ Negative 14 46 0.107*

Grade 1 23 55

Grade 2 12 12

Grade 3 1 4

FOX-P3+ Numbers 5.8±6.0 2.1±3.6 <0.001†

Negative 12 62 0.001*

Positive 38 55

CD68+ Negative 6 11 0.717*

Grade 1 18 53

Grade 2 22 46

Grade 3 4 7

CD8 and CD68 cytoplasmic and membrane expression levels were graded on a scale of 0 to 3 based on the proportion of positive mononuclear cells infiltrated in the intratumoral and peritumoral stromal tissue. Arbitrary cutoff points at 1% (grade 0), 5% (grade 1), 25% (grade 2), and 50% (grade 3) for each positive cell per infiltrated immune cells were used. FOX-P3 nuclear expression was counted as positive mononuclear cells in 3 high power fields (x400) in each tumor core.*Chi-square test. †Independent t-test.

Table 5. Multivariate analysis using Cox regression hazard model (non-stepwise) with regard to overall survival

Variable OR (95% CI) p-value

Age 1.058 (1.022-1.095) 0.001

Stage III 22.436 (2.608-193.004) 0.005

Optimal debulking surgery (no macroscopic residual) 0.184 (0.037-0.921) 0.039

Well differentiated 0.177 (0.033-0.946) 0.043

Tumor size 1.067 (1.004-1.134) 0.038

Lymphovascular involvement 0.822 (0.319-2.113) 0.683

Cytology 1.547 (0.687-3.484) 0.292

Ascites 0.671 (0.248-1.810) 0.430

CA-125 1.000 (0.999-1.000) 0.256

CA 19-9 1.001 (1.000-1.001) 0.124

CD73 overexpression 1.025 (0.460-2.287) 0.951

CD8+ cells infiltration 1.335 (0.567-3.142) 0.509

FOX-P3+ cells infiltration 0.985 (0.900-1.077) 0.740

CD68+ cells infiltration 2.764 (0.668-11.442) 0.161

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hostimmunologicresponseagainsttumorcells,ourfindingisunexpected.ThereasonforalackofdifferenceinCD8+T-cellinfiltrationlevelsbetweenthetwopatientgroupsispresentlyunknown.Similarly,wefoundnodifferenceintheinfiltrationstatusofCD68+cells(monocytes/macrophages)betweenthetwopatientgroups.Inthisstudy,CD73overexpressionwasmorefrequentlyob-

servedinepithelialovariancancerpatientswithknowngoodprognostic factors, includingwell/moderatedifferentiationandlowerstage.Thesefindingsshowthatdifferentiationsta-tusandstagehavemoreinfluenceonthesurvivaloutcomethantheadverseeffectofCD73on immunologicenviron-ment.BecausetheeffectofCD73targetingtherapywillbelimitedtopatientswithepithelialovariancancerwithCD73overexpression,CD73targetingtherapywillnotbebenefi-cialtopatientswithpoorlydifferentiatedovariancarcinomawithoutCD73expression.Thelimitationsofthecurrentstudyincludethefactthatitwasaretrospectivestudy,ithadalim-itednumberofenrolledpatients,anditdidnotevaluatethefunctionsoflymphocytes.

CONFLICT OF INTEREST

Nopotentialconflictof interestsrelevanttothisarticlewasreported.

ACKNOWLEDGMENTS

ThisworkwassupportedbythegrantofResearchInstituteofMedicalScience,CatholicUniversityofDaegu(2010).

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