Engineering5(2019)132–139Contents lists available at ScienceDirectEngineeringResearch
Immunology—Review
RegulatoryTCellsandTheirClinicalApplicationsinAntitumorImmunotherapy
FengXiea,b,RuiLianga,b,DanLia,b,?,BinLia,b,?abShanghaiInstituteofImmunology,ShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai200025,ChinaDepartmentofImmunologyandMicrobiology,ShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai200025,Chinaarticleinfoabstract
Cancer is a potentially life-threatening disease characterized by the immortalization of tumor cells in the host. Immunotherapy has recently gained increasing interest among researchers due to its tremendous potential for preventing tumor progression and metastasis. Regulatory T cells (Tregs) are a subgroup of suppressive CD4+ T cells that play a vital role in the maintenance of host immune homeostasis. Treg de?ciency can induce severe autoimmune, hypersensitivity, and auto-in?ammatory disorders, among other diseases. Tregs are commonly enriched in a tumor microenvironment, and a greater number of immune-suppressive Tregs often indicates a poorer prognosis; therefore, there is renewed interest in the function of Tregs and in their clinical application in antitumor immunotherapy. Accumulating strategies that focus on the depletion of Tregs have appeared to be effective in antitumor immunity. It is expected that Treg-targeting strategies will provide great opportunities for improving antitumor ef?ciency in combination with other therapeutics (e.g., chimeric antigen receptor T cell (CAR-T)-based cell therapy or immune checkpoint blockading).
ó 2019 THE AUTHORS. Published by Elsevier LTD on behalf of Chinese Academy of Engineering and Higher Education Press Limited Company. This is an open access article under the CC BY-NC-ND license
Articlehistory:Received23July2018Revised8November2018Accepted7December2018Availableonline29December2018Keywords:RegulatoryTcellsCancerImmunotherapy1.IntroductionCancerisaglobalpublichealthproblemthatcausesthedeathoftensofthousandsofpeopleeachyear.Despiteenormouseffortstodevelopeffectivetreatmentstrategies,nosatisfactoryresultshaveyetemerged,andtheoverallsurvivalrateanddisease-freesurvivalofmostcancersremainpoor.Althoughconventionaltreat-ments,includingradiotherapy,chemotherapy,surgicaloperation,andmolecular-targetedtherapy,areeffectiveinattackingtumorcells,theysimultaneouslycreatelife-threateningsideeffects.Themostcommonadverseeffectsincludegastrointestinalreactionandbonemarrowsuppression,whichnotonlyin?uencethepostoperativequalityoflife,butcanalsoleaddirectlytodeath[1].Inthelastdecades,immunotherapyhasbeenanactiveareaofresearchintumortherapy,andconsiderableeffortshavebeenexpendedinthis?eld.Thesenewstrategies,whicharerepresentedbyimmunecheckpointinhibitors(e.g.,programmeddeath1(PD-1),programmeddeathligand1(PD-L1),andcytotoxicTlymphocyte-associatedantigen4(CTLA-4))andchimericantigenreceptorTcell(CAR-T)immunotherapy,haveshowninspiringef?cacyinaddressingvarioustypesofcancer[2–8].Unfortunately,anincreasingnumberofstudieshavedemonstratedthatonly20%–30%ofpatientsrespondtothesestrategies[9],bringingupthequestionofwhyimmunotherapieshavefailedin70%–80%ofpatients.Oneexplanationthathasbeenacceptedisthattumorshaveevolvedanimmune-suppressingnetworktopreventattacksfromimmunesystems.RegulatoryTcells(Tregs)areanimportantpartofthisnetwork.TregsthatstronglyexpressCD25(interleukin(IL)-2receptora-chain)andforkheadboxP3(FOXP3)areenrichedinthetumormicroenvironment,andprimarilycompriseanimmunosuppressivenetwork[10].Here,wefocusonthecriticalrolesplayedbyTregsintumorimmunosuppressingnetwork,andontheirtherapeuticpotentialtotreatdiversetypesoftumor.2.TregdifferentiationanddevelopmentBasedontheirorigins,Tregscanbecharacterizedintotwopopulations.The?rstclassofTregsarenaturalregulatoryTcells(nTregs),whichdifferentiatefromthethymusandareinducedbyabroadspectrumofautoantigens[11];forthisreason,nTregsarealsoknownasthymus-derivedTregs(tTregs).Afterbeing?Correspondingauthors.E-mailaddresses:danli@shsmu.edu.cn(D.Li),binli@shsmu.edu.cn(B.Li).F.Xieetal./Engineering5(2019)132–139133stimulatedbythemajorhistocompatibilitycomplex(MHC)–autoantigencomplex,afractionofCD4+CD8+TcellsinthymocytesstarttoexpressCD25,throughwhichIL-2inducestheproductionofFOXP3viasignaltransducerandactivatoroftranscription5(STAT5)[12].TheotherclassofTregcomprisesinducedregulatoryTcells(iTregs),whicharealsoknownasperipherallyderivedTregs(pTregs).Manyfactors(e.g.,transforminggrowthfactorb(TGF-b),dendriticcells(DCs)expressingindoleamine2,3-dioxygenase(IDO),orretinoicacid)canconvertperipheralCD4+naiveTcellsintoiTregs[13–15].BothsubsetshavesimilarsurfacemarkersandconsiderablesuppressivefunctionagainsteffectorTcells(Teffs).However,accumulatingevidencehasshownthattherearemanydifferencesbetweenTregsubsets,suchasdifferentproteinexpressionandepigeneticmodi?cation.Forexample,iTregsreportedlyexpressalowlevelofHeliosandNeuropilin-1(NRP1),whereasnTregsareabundantinthesemolecules[16,17].Inaddition,therearetwootherspecialsubsetsofTregsthatdonotexpressFoxp3:IL-10-producingTregulatorytype1(Tr1)cellsandTGF-b-producingThelpertype3(Th3)cells[18].IntheprocessofTregdevelopment,Tcellreceptor(TCR)signalisindispensable,suchthatblockageofTCRleadstosuppressedTregdevelopment[19].Tcellswithahighaf?nitytoautoantigensundergonegativeselectioninthethymus,leadingtoapoptosis,whereasTcellswithalowaf?nityforautoantigenssurviveanddevelopintoTeffs.Thethresholdofaviditythatisselectedtopro-ducenTregsisbetweenpositiveandnegativeselection[20].Inaddition,Tregdevelopmentrequiresco-stimulatorymoleculessuchasCD28andglucocorticoid-inducedtumornecrosisfactorreceptor(TNFR)-relatedprotein(GITR).PreviousstudieshaverevealedthatinmicelackingCD28orCD80/CD86,theTregnumberisdecreased[21,22].AnotherindispensablefactorforTregdevel-opmentisIL-2.Tregsremainnon-responsivetohigh-doseIL-2,solid-coatedorsolubleanti-CD3monoclonalantibodies(mAb),oracombinationofanti-CD3mAbandanti-CD28mAb.OnlywhenaTCRsignalandahighconcentrationofexogenousIL-2aresimul-taneouslypresentcanaTregbeactivated;however,theprolifera-tionisweakerthanthatofCD4+CD25–Tcells[23].Infact,anegativeloopispresentinwhichantigen-activatedTcellsproduceIL-2toinducetheproliferationofTregs,whichthenmountasup-pressoryresponseagainsttheseactivatedTcellsinordertoavoidoverreaction.Thenuclearfactor-jB(NF-jB)signalingpathway,downstreamofTCR/CD28,alsoplaysacriticalroleinTregdevelop-ment.UnderconditionsofTCR/CD28co-stimulation,C-RELbindstothepromoterandconservesnon-codingDNAsequencesoftheFoxp3geneinordertoregulateFoxp3transcription[24].Medullarythymicepithelialcell(mTEC)signalingisalsoanimportantfactorinregulatingthedevelopmentofnTregs.Ade?ciencyinTNFR-associatedfactor6(TRAF6)impairsthematurationofmTECs,andtherebyinhibitsTregdevelopment[25].Inamousemodelofcancer,researchersfoundthatNRP1playsavitalroleinmaintain-ingthefunctionoftumor-in?ltratingTregs.SelectiveknockoutofNrp1inmiceresultsinalossoffunctionofTregs.Themechanismunderlyingthisphenotypeisthattheinterferon-c(IFN-c)pro-ducedduetoade?ciencyinNrp1drivesthefragilityoftumor-in?ltratingTregs[26].Inthisregard,itisnotablethatalackofNrp1simplyin?uencestheantitumorfunctionofTreg;itsroleinavoidingautoimmunitydiseaseisnotaffected.3.TregfunctionregulationFOXP3isamasterregulatorinthedevelopmentandfunctionofTregs[27].TheimportanceofFOXP3ishighlightedbythepro-foundlossofnTregsinFoxp3-knockoutmice.Inaddition,theadop-tivetransferofFoxp3canconvertperipheralCD4+CD25–TcellsintoiTregs.Bothofthese?ndingsindicatethatFoxp3isasinequanoninTregdevelopment.Foxp3expressionisregulatedbyaseriesofphysiologicalsignalsandproteinmodi?cations.However,inaddi-tiontoTregs,therearemultiplecelltypesthatexpressFoxp3butlackasuppressivefunction,includingepithelialcellsofthebreast,lung,andprostate[28].ThisdemonstratesthattheexpressionofFoxp3isinsuf?cientforestablishingtheTregcelllineage.Further-more,insomecases,FOXP3–cellsalsopossessapotentinhibitoryfunction[29].AnincreasingamountofevidencehasrevealedthattherearetwoindependenteventsintheprocessofTregdevelop-ment:theexpressionofFoxp3andthemodi?cationofFoxp3[30].3.1.RegulationofFoxp3atthetranscriptionallevelFoxp3geneexpressioniscontrolledbyfourelements:thepro-moterregion;twoconservednon-codingsequences(CNS1andCNS2)withinthe?rstintron;andthesecondintron,whichcon-tainsCNS3[31].CNS1containsbindingsitesforactivatorprotein1(AP-1),mothersagainstdecapentaplegichomolog3(SMAD3),andthenuclearfactorofactivatedTcells(NFATs).InCNS1-knockoutmice,theexpressionofFoxp3intTregsiscomparablewiththatinwild-type(WT)mice,whileiTregisreduced;this?nd-ingrevealstheroleofCNS1intheperipheralinductionofTregs.CsA(aninhibitorofNFAT)andSIS3(aninhibitorofSMAD3)canresultinalossofFoxp3expression[32].CNS2,whichcontainsbind-ingsitesforSTAT5[33],cyclicadenosinemonophosphate(cAMP)responsiveelement-binding(CREB)/activatingtranscriptionfactor(ATF)[34],forkheadboxproteinO1(FOXO1),andforkheadboxproteinO3(FOXO3)[35],istermedas‘‘Treg-speci?cdemethylatedregion”(TSDR),becausethisareainnTregsiscompletelydemethy-lated.CNS2-de?cientmicedemonstrateadecreasednumberofTregsaftersixmonths,suggestingthatCNS2isessentialinthemaintenanceofstabilitybutdispensableintheexpressionofFoxp3[32].CNS3isboundbyC-REL,whichactsasachromatinopenertopromotetheformationofaFoxp3-speci?cenhanceosome;thenumberofTregsisreducedinCNS3à/àmice[24].3.2.Post-modi?cationofFoxp3inTregsPost-translationalmodi?cationofFoxp3inTregsiscomprisedofubiquitination,acetylation,methylation,poly(ADP-ribosyl)ation,andsoforth.Underin?ammationelicitedbypro-in?ammatorycytokinesandlipopolysaccharide,TregswilldownregulatetheexpressionofFoxp3,thuspermittingthegainofTeff-likefunctions[36].Themechanismunderlyingthisphenotypeisasfollows:Dur-ingin?ammation,theE3ubiquitinligaseStub1isactivatedandinducesthedegradationofFOXP3inanHsp70-dependentmanner.Incontrast,ubiquitin-speci?cprotease7(USP7)andubiquitin-speci?cprotease21(USP21)aretwomajorde-ubiquitinenzymesthatarecapableofreducingthenumberandfunctionofTregs[37,38].ThebalancebetweenlysineacetylationanddeacetylationisanotherfactorthatplaysanessentialroleinregulatingthestabilityandfunctionofFOXP3proteins.Thehistoneacetyltransferases(HATs)TIP60[39]andp300[40]canstabilizetheFOXP3protein,thuspromotingitsinhibitoryfunction,viaFOXP3acetylation.Here,nicotinamideadeninedinucleotide(NAD)-dependentdeacetylasesirtuin-1(SIRT1)hasanoppositeroletothoseofTIP60andp300[41].ComparedwithconventionalTcells,CNS2andFoxp3pro-motercontainahighlydemethylatedregionthatisindispensableinmaintainingthestabilityofFoxp3expression[42].MethylationoftheCREB/ATFsiteinthe?rstintronshowsanegativecorrelationwithFoxp3expression.Therearemanyotheradjustmentmethodsaswell,suchasphosphorylationandsmallubiquitin-likemodi?er(SUMO)modi?cation.Thisisacomplicatedprocessregulatedbymultipleelements.134F.Xieetal./Engineering5(2019)132–1394.Tregfunctionsandsuppressivemechanisms4.1.SuppressivemechanismsofTregsTherearediversemechanismsbywhichTregsexerttheirsup-pressoractivity(Fig.1).Amongthese,someproposedmechanismsarelistedbelow.4.1.1.SecretionofTregsTregscansecretvariousinhibitorycytokinessuchasIL-10,TGF-b[43],andIL-35[44].Atpresent,theviewthatIL-10andTGF-bmayparticipateintheregulatoryactivityofTregsisstillcontrover-sial.IL-10andTGF-bcanrelieveintestinalin?ammationcausedbyTregde?ciency[45].However,neutralizationofIL-10andTGF-binvitrodoesnotimpairtheinhibitoryeffectofTregs[46].Collisonetal.[44]havedemonstratedthattheco-cultureofTregsandTeffsleadstoupregulationofIL-35,consistingofEpstein-Barrvirusinducedgene3(EBI3)andIL-12A,andthattheectopicexpressionofIL-35cansuppressthefunctionsofTeffs.IthasnowbeenwellsubstantiatedthatIL-35contributestoabrogationofin?ammatoryboweldiseaseandpsoriasis[47].NeutralizationofIL-35canexertalimitationontumorgrowthinmultiplemurinemodelsofhumancancer[48].Furthermore,TregcanbeimmunesuppressivebysecretinggranzymeB(GZ-B).GZ-Bisaserineproteasewiththeabilitytoinduceapoptosisintargetedcells[49].ComparedwithWTmice,theTregsderivedfromGZ-Bà/àmicehavealowersuppressiveability[50].4.1.2.DirectcontactbetweencellsTregscanalsofunctionthroughdirectcontactbetweencellsviaTGF-b,CTLA-4,GITR,andgalectin-1.CTLA-4isaco-inhibitorymoleculeexpressedbybothTregsandTeffs.ActivationofTeffsrequiresco-stimulatorysignalssuppliedbyacombinationofCD28andCD80/CD86.Af?nityofCTLA-4ishigherthanthatofCD28,thusrestrainingcombinationbetweenCD28andCD80/CD86[51–53].GITRisaco-stimulatorymoleculethatisconstitutivelyoverexpressedinCD4+CD25+Tregs.GITR-knockoutmiceshowanimpairedTregfunction[54].Galectin-1,whichbelongstothefamilyofb-galactoside-bindingproteins,isanegativegrowthfactorthatregulatescellproliferation.Galectin-1secretedonthesurfaceofTregsinteractswithTeffs,destroyingtheircellcycleprogressandthusinducingtheirapoptosis.Blockadeofgalectin-1reducestheef?cacyofTregsinbothhumanandmice[55].4.1.3.ExtracellularadenosinetriphosphateTheextracellularadenosinetriphosphate(ATP)producedbydamagedcellsactsasa‘‘naturaladjuvant”inin?ammationreactions.ExtracellularenzymesCD39andCD73candegradeATPtoadenosinemonophosphate(AMP)andproduceadenosine(aninhibitorofTeffactivation)[56,57].4.1.4.CompetitionbetweenTregsandconventionalTcellsIL-2isagrowthfactorrequiredbybothTregsandTeffs.TregscannotproduceIL-2itselfbecauseoftheexpressionofkeytran-scriptionfactorFOXP3,whichisatranscriptionalrepressoroftheFig.1.SuppressivemechanismsofTregs.GITRL:GITRligand;LAG3:lymphocyteactivationgene3protein;GZ-B:granzymeB;TIGIT:Tcellimmunoglobulin(Ig)andimmunoreceptortyrosine-basedinhibitionmotif(ITIM)domain.F.Xieetal./Engineering5(2019)132–139135IL-2gene.Therefore,competitionbetweenTregsandconventionalTcellsisoneofthemechanismsunderlyingTregsuppressiveef?cacy[58].4.1.5.DendriticcellsDCsareantigen-presentingcellsresponsibleforthepresenta-tionofantigenstoTcells.TregscaninteractwithDCsvialympho-cyteactivationgene3protein(LAG3)[59],T-cellimmunoglobulin(Ig)andimmunoreceptortyrosine-basedinhibitionmotif(ITIM)domain(TIGIT)[60],andNRP1[61]toinducetheproductionofimmunosuppressiveIDO[62].IDOdegradestryptophanandleadtoapoptosisinTcells.4.1.6.OxidativestressTregsintumorsundergodeathunderoxidativestress.ItisnotablethatapoptoticTregsarestillimmunosuppressive,whichpresentsachallengetoantitumorimmunotherapytargetingTregs.Themechanismmaybeduetothereleaseoflargeamountsofsmallmetabolites(e.g,ATP).Ingeneral,ATPishelpfultothehost;however,TregsinasuddendeathstatequicklyconvertATPtoadenosine,whichthenbindstoreceptorsontheTcellsurfaceandaffectsTcellfunction[63].4.2.TregfunctionsintumorsThebest-knownfunctionofTregsisthatofsuppressing.Thatis,afterbeingstimulatedbyaTCRsignal,TregspossessthecapacitytoinhibittheactivationandproliferationofmultiplecellsincludingTeffs,Bcells,naturalkiller(NK)cells,andDCs.Moreover,theimmunosuppressiveeffectsofTregsarenotantigenspeci?candarenotrestrictedbyMHC.Numerousstudieshavedemon-stratedthatTregsparticipateinhomeostaticregulationandtumorimmuneescape.TheoverwhelmingevidencefrommultiplestudiesinbothmiceandhumansindicatesthatadoptiveTregtransferscanreverseautoimmunediseasethatisinducedbyTregde?ciencyorFoxp3mutation[64–66].Therefore,Tregsareessentialandindis-pensableinprotectingthehostfromdysregulation.Intumors,ithasbeenrecognizedthattheabundantpresenceofTregsoftenindicatespoorprognosis[67].Inordertoidentifythecommonbasisbetweentumorimmunityandautoimmunity,Shimizuetal.[10]demonstratedthatremovingTregsviaanti-CD25antibodycaneffectivelyalleviateavarietyofinoculatedsyngeneictumors.However,recentnewstudieshavechallengedtherelationshipbetweenTregsandtumorprognosis.ResearchershavefoundthatbasedontheexpressionofFoxp3andCD45RA,Tregscanbeclassi?edintothreetypes:naiveTregs(FOXP3loCD45RA+),effectorTregs(FOXP3hiCD45RA–),andnon-Tregs(FOXP3loCD45RA–).NaiveTregsareonlyweaklysuppressive,whileeffectorTregs,whichdifferentiatefromnaiveTregsafterantigenicstimulation,possessstrongsuppressiveactivityandstablefunction.Non-Tregscannotexertaninhibitoryeffectbutcansecretepro-in?ammatorycytokines.Basedonthisclassi?cation,colorectalcancer(CRC)hasbeenseparatedintotwotypes,oneofwhichispredominantlyin?ltratedbyeffectorTregs,whiletheotherisabundantinnon-Tregs.Intheformergroup,Tregsindicateapoorprognosis;however,inthelattergroup,patientswithmoreTregin?ltrationinthetumormicroenvironmenthaveabetterprognosis[68,69].Infact,theappearanceofTregsisnotalwaysharmful.Strongevidencesupportsthenotionthatchronicin?ammatorydiseasepromotestheprogressionofcertaintypesofcancerssuchascoloncancer,livercancer,andpancreaticcancer.Thus,methodstarget-ingthein?ammatorynetworkofthetumorenvironmentmaybeabletooffertumorpreventionandtreatment[70].Tregsareoneofthemainanti-in?ammatoryfactors.EpidemiologicaldatahaverevealedthatindividualsexposedtodiverseenvironmentalorganismsmaintainaprotectiveTregphenotypethatpreventscancer,whereashygienicindividualswithlittleexposureearlyinlifesufferanincreasedriskofmalignancylaterinlifeduetoadys-regulatedTregfeedbackloop[71].Furthermore,anincreasingnumberofstudieshaverevealedotheruniquefunctionsofFOXP3+Tregs.Onesuchfunctionisreg-ulatingtheadipose-associatedin?ammationandmetabolicpro-cessthroughtheperoxisomeproliferator-activatedreceptor-c(PPAR-c)andIL-33–suppressionoftumorigenicity2(ST2)axis[72,73],whichmaypromotetissuerepairinnon-lymphoidorgansviathesecretedcytokineamphiregulin(Areg)[74,75]orstimulatethedifferentiationofstemcells[76].These?ndingsprovidenewpossibilitiesthattherolesoftumor-associatedTregsmaybediverse;newstudiesfocusingontheseadditionalfunctionsmayrevealtherapeutictargetsforantitumorclinicalstudies.5.ImmunecellsandthetumormicroenvironmentOneoftheprominentfeaturesoftumorcellsistheirunlimitedcapabilityforproliferation,whichleadstoalargeenergydemand.TherearetwomajorpathwaysforcellstogainATP.Oneisthegly-colysis(Gly)ofglucoseincytosol,andtheotheristheoxidativephosphorylationofglycosidesinmitochondriaviathetricarboxylicacid(TCA)cycle.TumorcellspreferentiallyselecttheglycolyticpathwaytoobtainATPandotherformsofenergy,eveninanaer-obicenvironment,whichisknownastheWarburgeffect[77].Throughtheglycolyticpathway,tumorcellsproducealargenum-berofmetabolitessuchaslacticacidandcarbondioxide.TheseproductsnotonlyinhibittheeffectofconventionalTcells,butalsoinhibitthematurationandactivationofDCs.Thereasonisthatantitumorimmunecells(suchascytolyticTlymphocytes(CTLs),Teffs,andactivatedDCs),liketumorcells,obtaintherawmaterialsneededforenergyandbiosynthesisthroughaerobicGlyandglu-taminedecompositionpathways[78].However,Tregspreferthefattyacidenergysupplypathway,andcanusethemetabolitesofneoplasmstoobtainenergy[79].Thus,tumorcellsproliferateinanimmunosuppressivenetworkinwhichTregsareabundant,butTcellsandDCslosetheirfunction.Changetal.[80]havefoundthattumorcellandTcellmetabolismofglucoseinthetumormicroenvironmentcaninhibittheactivationofthemammaliantargetofrapamycin(mTOR)signalingpathwayofTcellsanddecreasethenumberofIFN-c,therebycausingTcellstoexhibitlowreactivityinthetumormicroenvironment.Giventhese?nd-ings,itissuggestedthatinatumorenvironment,Tregsformasymbioticrelationshipwithtumorcells.Otherthanmetaboliccauses,therearemanyothertriggersofTregaggregationinthetumormicroenvironment.Tumorcellsandin?ltratingmacrophagescansecreteavarietyofchemokines(e.g.,CCchemokineligand22(CCL22)/CCchemokinereceptor4(CCR4)[81]andCXCmotifchemokine12(CXCL12)/CXCchemo-kinereceptor4(CXCR4)[82])torecruitTregs.Furthermore,DCsandsomesuppressorsincludingIL-10,TGF-b,andIDO,whichareenrichedinthetumorenvironment,areabletoconvertTeffsintoCD4+CD25+FOXP3+Tcellsandamplifythymic-derivedTregs.6.Uniquefeaturesoftumor-associatedTregsAnimprovedunderstandingoftheuniquefeaturesoftumor-in?ltratingTregsisofgreatimportancefortherapeuticbene?t.Plitasetal.[83]havefoundthatrelativetonormalbreastparenchyma(NBP)andperipheralblood,tumor-residentTcellsexhibitanincreasedabundanceandhighlyproliferativephenotypeofFOXP3+Tregs.Furthermore,moreadvancedgradesandmoreaggressiveformsofbreastcancerappearedtocontainaheightenedpresenceofactivatedTregswithpotentsuppressorfunction.RNA-seqanalysisofpuri?edCD25hiCD4+TregsandCD25–CD4+136F.Xieetal./Engineering5(2019)132–139Teffsindicatedthatthegeneexpressionpatternsoftumor-residentTregsandTeffscellsweredistinctfromthoseofcorrespondingcellsisolatedfromperipheralblood.Detailedanalysishasidenti?edchemokine(C–Cmotif)receptor8(CCR8)asthemostrobustlyanddifferentiallyexpressedchemokinereceptorinbreasttumor-residentTregs.ThecorrelationofahighCcr8/Foxp3mRNAexpressionratiowithmarkedlydecreaseddisease-freeandoverallsurvivallevelswasobservedaswell;together,these?ndingsindi-catethatCCR8mayserveasapromisingtargetforantitumorimmunotherapy.TheobservedprotectiveantitumorimmunityinsubsequentresearchthattargetedCCR8incoloncancerstronglyindicatedthebiologicalimportanceofthisreceptor[84].SeveralgenesnotpreviouslyimplicatedinTregsbiologywerealsofoundtoberobustlyexpressedbytumorTregs,suchasthemelanomaantigenfamilyH1(MAGEH1)geneandCD177.Inparallelstudies,bothDeSimoneetal.[85]andZhengetal.[86]foundaseriesofgenesthatwerepreferentiallyupregulatedbyintra-tumoralTregs.Itisnotablethat31ofthedifferentgeneswereidenti?edinallthreestudiescitedabove,includingCTLA-4,tumornecrosisfactorreceptorsuperfamily,member4(OX40),GITR,4-1BB,TIGIT,ICOS,andCD27.However,becausethesecellsurfacemarkersarealsoexpressedinafractionofnon-tumor-in?ltratingTregs,thefunc-tionalconsequencesforantitumorimmunotherapyagainstthesereceptorsremainunclear.7.Tregsinantitumorimmunotherapy7.1.CheckpointblockadesassociatedwithTregsClinicalusageofimmunecheckpointinhibitors,suchasCTLA-4,PD-1,andPD-L1,caninducerobustanddurableresponsesinmanycancertypes.IntumorpatientstreatedwithIpilimumab,ablock-adeofCTLA-4,thenumberofTregsin?ltratingthetumorwasreduced[87,88].Furthermore,theCTLA-4signalisessentialforbothTregsandTeffs,sothatadministrationoftherapeuticanti-CTLA-4antibodynotonlyattenuatestheimmune-suppressivefunctionofTregs,butalsoaugmentsTeffresponse[89].Inaddition,themechanismsofanti-CTLAantibodieshaverecentlybeenchal-lengedbyincreasedresearchesthatdemonstratethattheseanti-bodiesmayfunctionbyinducingantibody-dependentcellularcytotoxicity(ADCC),ratherthanbyblockinginhibitorycheck-points.Itisnoteworthythatinmanytypesofcancers,suchasCRC,immune-suppressiveTregsmayplayacriticalroleinrestrict-ingcancerprogression;therefore,thedepletionoftumor-in?ltratingTregsinthesecancerscouldbeunadvisable.Theroleofanti-PD-1antibodyinblockingTregshasnotyetbeendeter-mined.Inamousemodel,ithasbeenreportedthatthesuppressivefunctionofPD-1-expressingTregsishigherthanthatofTregswithoutPD-1expression[90](Fig.2).Fig.2.ThediversefunctionofTregsinantitumorimmunotherapy.PI(3)K:phosphatidylinositol3-kinase;PIP3:phosphatidylinositol(3,4,5)-trisphosphate;OX40L:ligandforOX40;AKT:Aktserine/threoninekinase1.
调节性T 细胞及其在抗肿瘤免疫疗法中的临床应用 - 图文
