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肿瘤微环境简介苏州大学免疫学系居颂光？SidP.KerkarandNicholasP.Restifo.CancerRes2012;72:3125-3130.肿瘤微环境如果仅仅关注肿瘤细胞，那我们在盲人摸象肿瘤研究≠肿瘤细胞研究一个世纪的观念：肿瘤是局部组织/器官细胞异常生长形成的疾病肿瘤是个系统性疾病肿瘤是一种组织（间质、血管、微环境），不是一堆肿瘤细胞免疫功能失控，肿瘤患者的免疫系统不是简单的低下：保护肿瘤生长的免疫细胞：功能增强抑制肿瘤细胞的免疫细胞：功能低下肿瘤的免疫编辑免疫成分在肿瘤发生过程中的作用DunnG,etal.Natureimmunology.2002.3(11):991EliminationcorrespondstoimmunosurveillianceThehostimmunesystemandanytumorvariantthathassurvivedintheeliminationprocessenterintothedynamicequilibrium:*lymphocytesandIFN-γexertpotentselectionpressure.*Atumorbediscontainingmanygeneticallyunstableandrapidlymutatingtumorcells.Survivaltumorvariantsthathaveacquiredinsensitivitytoimmunologicdetectionand/oreliminationbegintoexpandinuncontrolmanner.DunnG,etal.Natureimmunology.2002.3(11):991Solidtumorsreachacertainsize:Growinvasively,requireanenhancedbloodsupply.Inflammatorysignalsleadingtorecruitmentofcellsofinnateimmunesystem:macrophages,DCs,γδ-T,NKandNKT.ProduceIFN-γTheinitialIFN-γstartsacascadeofimmuneresponse:1.Inductionofchemokines:CXCL10,CXCL9,CXCL11.Blockneovascularizationoftumor,recruitmacrophages,DCs,γδ-T,NKandotherimmunecells.2.Antiproliferationofdevelopingtumor.3.TheactivationofcytocidalactivityinmacrophagesandNKcellsenteringthetumor.DeadtumorcellsortumorcellsdebrisareingestedbyDCandaretraffickedtothedraininglymphnode.1.TumorgrowthiskeptincheckbythecytocidalNKandmocrophages.2.CD4+TandCD8+Tcellsthatarespecificfortumorantigensaredevelopingindraininglymphnode.TumorspecificCD4+TandCD8+Tcellshometotumorsitealongachemokinegradient.DunnG,etal.Natureimmunology.2002.3(11):991EliminationcorrespondstoimmunosurveillianceThehostimmunesystemandanytumorvariantthathassurvivedintheeliminationprocessenterintothedynamicequilibrium:*lymphocytesandIFN-γexertpotentselectionpressure.*Atumorbediscontainingmanygeneticallyunstableandrapidlymutatingtumorcells.Survivaltumorvariantsthathaveacquiredinsensitivitytoimmunologicdetectionand/oreliminationbegintoexpandinuncontrolmanner.肿瘤细胞肿瘤抗原OliveraJ.Finn,Ph.D.NEnglJMed2008;358:2704-15OliveraJ.Finn,Ph.D.NEnglJMed2008;358:2704-15肿瘤抗原的加工提呈OliveraJ.Finn,Ph.D.NEnglJMed2008;358:2704-15肿瘤干细胞KnutsonK,etal.CancerImmunolImmunother2005,54:721–728APCTHTregCytoxicTcellsOthersIFNƔIL-2IL-12GranzymePerforinAbsothersTumormicroenvironment:NEnglJMed2006;355:1253-1261.CancerstemcellNatureReviewsCancerdoi:10.1038/nrc1232TumorHeterogeneityandCancerStemCells肿瘤微环境中的免疫稳态失衡•Nature.2005,5:263肿瘤患者的免疫状态是有别于正常人的免疫稳态的。肿瘤微环境中的免疫细胞TH17cellsintumourimmunityandImmunotherapy.NATuREREVIEWS|Immunology.doi:10.1038/nri2742DifferentiationofhelperTcellsubsetsTH17cellsandantitumourimmunity肿瘤微环境中的抑制性成分——Treg细胞Treg细胞定义•1995由Sakaguchi等发现了机体重要的负性免疫调节成分——调节性CD4+CD25+T细胞（regulatoryTcell,Treg）。随后的研究根据细胞内标记分子Foxp3和细胞膜分子CD127表达与否，将经典的Treg细胞定义为CD4+CD25+Foxp3+CD127low/negT细胞。•通过细胞间接触依赖机制发挥作用或分泌IL-10和TGF-β等细胞因子，Treg细胞抑制CD4+25-T细胞、CD8+T细胞和树突状细胞等其他免疫细胞的活性和功能。•大量的研究报道表明:CD4+CD25+Treg细胞是抑制机体抗肿瘤免疫应答的关键成分之一，例如：•Woo等发现在非小细胞肺癌和卵巢癌患者的肿瘤浸润淋巴细胞中Treg的含量明显增多；•在胃肠道肿瘤患者中CD4+CD25-T细胞明显减少而Treg细胞数量增多，而且Treg细胞数量的增高与较差的预后和较低的生存率高度相关；•Curiel等报道，在卵巢癌中Treg细胞能抑制T细胞介导的特异性抗肿瘤免疫应答，并且有利于肿瘤的生长；•因此研究者希望通过减少Treg细胞的数量或降低其活性来开辟治疗肿瘤免疫治疗的新途径。例如，以Foxp3为靶点清除荷瘤小鼠体内的Treg细胞后肿瘤会消退。Treg细胞的作用机制非小细胞性肺癌（NSCLC）与Treg新亚群Fig1Fig.2Fig3Fig4CD8+T细胞在肿瘤免疫中的作用肿瘤微环境中的“正性”免疫成分Gadd45β-/-miceorHet/WTmicewereinjectedintointradermallyofflankskinwith2.5X104B16cells/mouse.Tumorsizesweremeasuredevery2days.TumorinjectsiteGadd45bKOmicewerechallengedwithmelanomacells:B16Freezedownthetissueoftumorsite.Fig4Gadd45β-/-miceorWTmicewereinjectedsubcutaneouslywith2.5X104B16cells/mouse,tumorsizesweremeasuredevery2days.Thesedataarefrom3separatedexperiments.5.BothWTandGadd45bKOTcellsareabletoinfiltrateintotumorsites.Gadd45β-/-miceorWTmicewereinjectedintradermallyofflankskinwith5X104B16cells/site/20ulPBSSkinofinjectedsitesoroppositesiteswasresectedandfreezedownimmediatelySpleenCellsAdoptiveTransferandB16inoculationTumorinjectsiteChecktumorformationfrominjectedsites500RadWTKO500RadDonorHost6.Gadd45βisimportantforlymphocytesintumorsurveillanceP0.05*CD4+TCellsAdoptiveTransferandB16inoculation500RadWTCD4+TKOCD4+T500RadDonorHostWTsplenocytesdepletedCD4+TWTsplenocytesdepleteCD4+T++7.Gadd45bKOdoesnotaffectfunctionofCD4+TcellsintumorsurveillanceKO:TransferwithCD4+TcelldepletedspleencellsfromWTmice+CD4+TcellsfromGadd45bKOmicePBS:OnlytransferPBSWT:TransferwithCD4+TcelldepletedspleencellsfromWTmice+CD4+TcellsfromGadd45bHetorWTmiceCD8+TCellsAdoptiveTransferandB16inoculation500RadWTCD8+TKOCD8+T500RadDonorHostWTsplenocytesdepletedCD8+TWTsplenocytesdepleteCD8+T++8.Gadd45bKOcausesfunctiondefectofCD8+TcellsintumorsurveillanceKO:TransferwithCD8+TcelldepletedspleencellsfromWTmice+CD8+TcellsfromGadd45bKOmicePBS:OnlytransferPBSWT:TransferwithCD8+TcelldepletedspleencellsfromWTmice+CD8+TcellsfromGadd45bHetorWTmiceP0.05*Gadd45bisexpressedinCD8+TcellsduringtheiractivationFigure1Gadd45bmessageisinducedbyTCRsignalingandcostimulation.NaiveCD8+Tcellswerestimulatedwithplateboundanti-CD3(α-CD3)plusα-CD28andTh1conditionfor0h,1h,12h,24h,48hand96h.TheGadd45bmessagewasdetectedwithRT-PCR.2.Gadd45βisimportantfor