教学内容参考

14.Cancer14.CancerandImmuneAhiddenconnectionisstrongerthananobvious—HeraclitusofEphesus(535–475Reading:Kuby.Imminology.6thChaptor22:CancerandtheImmuneSystemImmImmImmImm教学 Immune Immunolactivities WorldCancerWorldCancerReport2014byCancerCancerandImmuneCancer:originandTumorimmuneresponsetotumorCancer1.Cancer:1.Cancer:originandMalignanttransformation恶性转化ofcellsbychemicalandphysicalcarcinogens致癌物orbytransformingvirus.Tumor：growthandmetastasis转Cancer：malignant•••1.1Typesof•Carcinoma:1.1Typesof•Carcinoma:arisingfromepithelialtissue,suchasglands,breast,skin,andliningsoftheurogenital,digestive,andrespiratorysystems(89.3%ofallcancers)源于上皮组织的恶性肿瘤Sarcoma:solidtumorsofmuscles,bone,andcartilagethat•fromtheembryological织的恶性•Leukemia:diseaseofbonemarrowcausingexcessiveproductionofleukocytes(3.4%ofallcancers)白血病Lymphoma,Myeloma:diseasesofthelymphnodesandthatcauseexcessiveproductionoflymphocytes(5.4%ofcancers)淋巴瘤髓瘤•1.21.2Hallmarksof1.3Tumor•Tumor1.3Tumor•Tumorimmunologyistostudytheimmunogenicity免疫原性oftumorandthemechanismofimmuneresponsetotumor;todemonstratetherelationshipbetweenthestatusofimmunesystemandthegeneration,developmentoftumor;toexplorethemethodoftumordiagnosis,therapyandprevention.•andmutanttorecognizeandclear2.Tumor•Tumor-2.Tumor•Tumor-Notuniquetotumorcellsbutalsopresentonnormal•2.1TumorTumor2.1TumorTumorantigens:Refertoallnewlyexpressedantigensoroverexpressedantigensduringthegenerationanddevelopmentofthetumor.AntigensencodedbygenesexclusivelyexpressedbyAntigensencodedbyvariantformsofnormalgenesthathavebeenalteredbyAntigensnormallyexpressedonlyatcertainstagesofdifferentiationoronlybycertaindifferentiationlineagesAntigensthatareoverexpressedinparticular①②③④BaseontheirpatternsofTumorspecificantigenTumorassociatedantigens2.1.1Tumor-specific2.1.1Tumor-specifictransplantationantigenTSA:Antigensthatareonlyexpressedontumorcellsbutnotonnormalcells.highspecificity.Tumorhigh-specificTSA---onlyexpressedononekindoftumor,inducedbyphysiochemicalfactors,suchasX-rayTumorlow-specificTSA---expressedonmorethanonekindoftumor,inducedbyDiscoveryoftumorDiscoveryoftumorspecifictransplantationantigens,ConclusionfromthisConclusionfromthis•Tumorsexpressantigensthatarerecognizedasforeignbytheimmunesystemofthetumor-bearinghost.ImmuneresponsefrequentlyfailtopreventthegrowthofTheimmunesystemcanbeactivatedbyexternalstimulatortoeffectivelykilltumorcellsanderadicatetumors.••2.1.2Tumor-associatedantigen•2.1.2Tumor-associatedantigen•Antigensthatarealsoexpressedonnormalcells,buthighexpressedontumorcellswithouttumorspecificitym,forexamplecarcinoembryonicantigenCEA,alpha-fetoproteinAFP.CEAisoneofembryonicantigensthatisexpressathighlevelsoncancercellsandinnormaldevelopingfetal,butpeteroutorverylowlevelinadult.CEAlevelsinnormalindividualsarebelow2.5CEAlevelofserumisincreasedincertainmalignancies,suchasthecolon,pancreas,stomach,andbreast.HighCEAlevelisnormallyrestrictedtocellsofthegut,pancreas,andliverinthecourseof2-6monthsofgestation,andlowlevelisfoundinserumofnormalThelevelofserumCEAisusedtomonitorthepersistenceorrecurrenceofthetumorsaftertreatment.Levels4-5-foldofnormalhavebeenusedtopredictrecurrenceofcolo-rectaltumors.Itmayalsoriseinsomenonmalignantconditions(e.g.,chroniccirrhosis,pulmonaryemphysema,heavysmoking).••••••AFPisacirculating•AFPisacirculatingglycoproteinnormallysynthesizedandsecretedbytheyolksacandliveroffetal.SerumlevelsofAFPisverylowinserumofadult(≤20ng/ml),andtheconcentrationofAFPisupto500ng/mlinserumofpatientswithhepatocellularhigherriseinthisproteinisusedformonitoringhepatomasandtesticularcancers.AFPlevelmayalsoberaisedinsomenonmalignantconditions,suchascirrhosis,hepatitisandotherformsofliverdamage.••Normalconcentration:<20Abnormal100-350possible350-500probable500-100likely>1000alpha-fetoproteinTumor(CancerTestisBreast&melaninDifferentiationTumor(CancerTestisBreast&melaninDifferentiation(TumorAssociatedlung,prostatelubsofcellColorectal(TumorSpecificHPVgeneproductCervical3.3.ImmuneResponsetoCell-mediatedImmuneHumoralimmuneMechanismofTumorImmune3.13.1Cell-mediatedImmuneResponse••••NKcellsDendriticcells(DCs)TNKTumorKumaretal.BasicPathologyed.FigureNKTumorKumaretal.BasicPathologyed.Figure6-1）NK1）NK•••NKcellsarebroad-spectrumkillerItcankilltargetcellswithlowlevelornonMHCclassⅠmolecule.Firstlineofdefenceofimmunesurveillance①②releaseof①②releaseoflysosomalenzymes,reactiveoxygenintermediates,nitricoxide③④secreteDendritic①APC------Induceadaptiveimmune②Inhibittumorgrowth4）TTTheprincipalmechanismoftumorimmunityiskillingoftumorcellsbyTIt’snon-classⅠMHCrestriction;ItstargetcellsarenothypersensitivetoNKcells.It’sthefirstlineofdefenceofimmunesurveillance.TumorDCcrossCD4+ThCD8+T3.3.2HumoralImmuneResponseto①Activating②③Antigen-specifictumorBcells(opsinization&NKcells&Antigen-specifictumorBcells(opsinization&NKcells&Antigen-specificTumorkilling:Antibody(ADCC,opsinization);Antigen-specificTumorkilling:Antibody(ADCC,opsinization);Tcells(cytokines,Fas-L,perforin/granzyme)IfIfCTLrecognizestumorcellspresentinghighlevelsoftumorantigen(A),granulereleaseandFasLcytolyticpathwaysaretriggeredresultingintumorcelldeath.Whenonlylowlevelsoftumorantigenarepresent(B),onlytheFasLcytolyticpathwayisactivated.3.3Mechanism3.3MechanismofTumorImmuneFactorsrelatedtotumor2)Factorsrelatedtothehost’simmuneSuppressingimmunefunctionbytumordirectlyor①②1).1).FactorsrelatedtotumorA.lowimmunogenicityoftumorantigensandantigeniclowimmunogenicityoftumorThefailureofimmunosurveillancemaybethefactthatintheearlydevelopmentofatumor,theamountofantigenmaybetoosmalltostimulatetheimmunesystem.antigenicmodulation:isaphenomenonthatcell-surfacetumorantigensaredecreaseorlosebecauseofattackofhost’shumoralimmune.LackLackCoveringCoveringorblockingoftumorantigensonthesurfaceofthetumorcells.DiminutionorabsenceofMHCclassILackofco-stimulatorymoleculeonthesurfaceoftumorImmuneinhibitorssecretedbytumorLackLackofco-2).Factors2).Factorsrelatedtohost’simmuneSuppressingimmunefunctionbytumordirectlyor①②•Cancer•CancerimmunesystemcanrecognizeanddestroynascenttransformedcellsCancerimmunesystemkillandalsoinducechangesintheresultingintumorescapeandrecurrence(epigeneticchangesorDarwinianselection)•4.Cancer1)4.Cancer1)Active2)Target3)Adoptive4)Cytokine5)1)Active1)ActiveStimulationofactivehostimmuneresponsesto•••Vaccinationwithtumorcellsandtumorantigens,orwithAPC.AugmentationofhostimmunitytotumorswithcytokinesandcostimulatorsNonspecificstimulationoftheimmune2)Target2)TargetUseoftumorspecific/associatedantigensmonoclonalTreatmentofTreatmentofB-celllymphomawithmAbspecificforidiotypicdeterminantsonthecancercells.BecauseallthelymphomacellsarederivedfromasingletransformedBcell,theyallexpressmembrane-boundantibody(Ab-1)withthesameidiotype.Monoclonalanti-idiotypeantibody(Ab-2)againsttheB-lymphomawasproduced(steps1–4).Whenthisantibodywasinjectedintothepatient(step5),itboundselectivelytoB-lymphomacells,whichthenweresusceptibletocomplement-plusantibodylysis.MonoclonalBrandApprovalMonoclonalBrandApprovalRituxan,3)Adoptive3)AdoptiveAdoptiveAdoptivecellularimmunotherapyisthetransferofculturedimmunecells(LAK,TIL,CD3AK,CTL)thathaveanti-tumorreactivityintoatumor-bearinghost.Use“primed”dendriticAPCscanbefedtumorantigensinthelaboratoryandtheninjectedintoapatient.Theinjectedcell