肿-瘤-微-环-境

肿瘤免疫中的正性和负性免疫成份居颂光细胞出版社以增刊方式向世界专门介绍中国免疫学研究•国际著名的细胞出版社（CellPress）近日推出新一期《聚焦中国》(SpotlightonChina)，介绍近年来中国免疫学基础及临床研究的飞速发展，其电子版在细胞出版社及其子刊的网站上均能免费阅读或下载。KnutsonK,etal.CancerImmunolImmunother2005,54:721–728APCTHTregCytoxicTcellsOthersIFNƔIL-2IL-12GranzymePerforinAbsothersTumormicroenvironment: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免疫成分在肿瘤微环境中的失衡•Nature.2005,5:263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+TcelldepletedspleencellsfromWTm