第11章+肿瘤与免疫

第十一章肿瘤免疫和免疫治疗TumorImmunologyandImmunotherapyOutlineTheimmunesystemImmunetoleranceImmunoeditingImmuneeliminationTumorantigenImmunoevasionImmunotherapyTheinnateandadaptiveimmuneresponseTheinnateimmuneresponsefunctionsasthefirstlineofdefenceagainstinfection.Theadaptiveimmuneresponseisslowertodevelop,butmanifestsasincreasedantigenicspecificityandmemory.TheimmunesystemInnateimmuneresponses:animmunesystemresponsestowardanantigenoranagentbearinganantigenthatoccursintheabsenceofpriorexposureofanorganismtothisparticularagentorcellAdaptiveimmuneresponses:animmunesystemresponsesthatisacquiredorlearnedfollowingexposureofanorganismtoanantigenorantigen-bearingagent•NeutralizationbyantibodymoleculesTheadaptiveimmuneresponseleadstoantibodyproductionAdaptiveimmuneresponse•Complement-mediatedkillingCoatingofpathogensbyantibodymoleculesandtheireliminationbyeffectoroftheimmunesystem•Antibody-dependentcell-mediatedcytotoxicity(抗体依赖性细胞介导的细胞毒作用,ADCC）•MechanismsofcellkillingbycytotoxiclymphocytesPerforinPinkarrow:aseriesoflyticgranulesinitscytoplasm—releaseperforinCylindricalchannelsintheplasmamembraneofthetargetAnotheradaptiveimmuneresponseleadstoformationofcytoxiccellsFasLonthesurfaceofTc—FasonthetargetcellTheinnateimmuneresponseNaturalkillercell(NKcell,自然杀伤细胞)LymphoidnullcellsthatlackthemarkerscharacteristicofotherlymphocytesanddonotrearrangeimmunoglobolinorTCRgenesarecalledNKcellSEM(scanningelectronmicrograph)RegulatoryTcells(TregcellsorTregS)areabletosuppressmajorcomponentsoftheadaptiveimmuneresponseOverviewofthehumoralandcellulararmsoftheimmunesystemTheneedtodistinguishselffromnon-selfresultsinimmunetoleranceTolerance:stateinwhichtheimmunesystemshowsalackofreactivitytowardcertainantigens,notablythosethatareexpressedbynormalcellsandtissues•Distinguishselffromnon-self•ThebreakdownoftolerancemayleadtoautoimmunediseasesNormalAutoimmunedestructionDestructionofnormaltissuesbyautoimmuneattackCancercells?Immunoediting—atypeofDarwinianselectionImmunosurveillance(免疫监视):processbywhichtheimmunesystemiscontinuouslymonitoringtissuesforthepresenceofaberrantcells,includingcancercells(Burnet,Thomas;1957)Cancerimmunosurveillance:theconceptofcancerimmunosurveillancepredictsthattheimmunesystemcanrecognizeprecursorsofcancerand,inmostcases,destroytheseprecursorsbeforetheybecomeclinicallyapparentTheimmunosurveillancetheorySyngeneic(同基因的,同系的)miceandMHCvariability•Allograft:implantationofcellsofananimalofonegeneticbackgroundintoahostanimalofanothergeneticbackgroundbutfromthesamespecies•Allograftrejection(同种异体移植物排异):situationarisingwhenadonortissuegraftisrejectedbytheimmunesystemofarecipientbecausethedonorandrecipient,althoughmembersofthesamespecies,aregeneticallydistinct•Syngeneic:referringtotwoorganismsthatsharetheidenticalgeneticbackground,suchastwomembersofaninbredstrainofmice•Allogeneic:referringtotwogeneticallydistinctmembersofthesamespeciesImmunizationofmicebyexposuretokilledcancercellsDemonstrationofimmunitytosyngeneictumorsUseofgeneticallyalteredmiceleadstoaresurrectionoftheimmunosurveillancetheory•RAG-1orRAG-2proteins:thesetwoproteinsareresponsibleforrearrangingthegenesencodingsolubleantibodymoleculesaswellasthoseencodingtheantigen-recognizingT-cellreceptors(TCRs)displayedonthesurfacesofTcells•SuchRAG-1orRAG-2-negativemicelackTlymphocytes,Blymphocytes,gdTcells,andasubclassofNKcellscalledNKTcellsBothwtandRAG-2-/-immunocompromisedmicewereexposedtothepotentcarcinogen3-MC(3-甲基胆蒽)•WhenthetumorsinducedintheRAG-2-/-miceweretransplantedbackintoRAG-2-/-hosts,theyallformedtumor(above)•WhenthetumorsinducedintheRAG-2-/-miceweretransplantedbackintowthosts,8of20failedtoform(below)ThetumorsthatdidariseinwtmicewerealreadyselectedforbeingweaklyimmunogenicandthuscapableofformingnewtumorsinotherwtmiceImmunoediting,theweedingoutofsometumorsandthetoleranceofothersImmunoediting:processwherebytheimmunesystempermitssomeweaklyimmunogenictumorstosurvivewhileselectivelyeliminatingthosethatarestronglyimmunogenicImmuneelimination:thehumanimmunesystemplaysacriticalroleinwardingoffvarioustypesofhumancancerCantheimmunesystemrecognizecancercellsarisinginaperson’sowntissuesasbeingforeign,eventhroughthesecellsaretrulynativetothebody?TheWinnassayTumor-infiltratinglymphocytes(TIL)OralcarcinomaTIL(brown,CD3antigen)UntreatedbreasttumorTIL(darkpurple,CD3antigen)ThetumorfollowingthechemotherapyTheclinicalprognosisofasetofovariancarcinomapatientsandTIL•CD8+cytotoxicTlymphocytes(CTLs)recognizeandkillstromaland/ortumourcellsinanMHC-restrictedandperforin-dependentmanner•Inparallel,theysecretetheanti-angiogeniccytokineinterferon-γ(IFNγ)•IFN-producingkillerdendriticcells(IKDCs)killtumourcellsinaTRAIL(tumour-necrosisfactor(TNF)-relatedapoptosis-inducingligand)-andperforin-dependentmanner.IKDCsarealsoamajorsourceofIFNγ.IKDCsmightalsocross-presenttumourantigenstoTcells.•IFN-producingkillerDC(IKDC).Adendriticcell(DC)thatexpressesmarkersofbothnaturalkillercellsandBcellsbutlacksmarkersofplasmacytoidDCsandTcells,aswellasco-stimulatorymolecules.TheseDCshavebeenisolated