20Tumorimmunolgy說課材料課件

Chapter20

TumorImmunologyIntroductionPartⅠ

TumorantigensPartⅡImmuneresponsetotumorsPartⅢMechanismoftumorescapefromimmunesurveillancePartⅣImmunotherapyoftumorsContentsChapter20TumorImmunologyTumorimmunologyismainlytostudytheimmunogenicityoftumorandthemechanismofimmuneresponsetotumor,todemonstratetherelationshipbetweenthestatusofimmunesystemandthegeneration,developmentoftumor,toexplorethemethodoftumordiagnosis,therapyandprevention.ImmunosurveillanceIntroductionBaseontheirpatternsofexpression:Tumorspecificantigen(TSA)Tumorassociatedantigens(TAA)Ⅰ.Classificationoftumorantigens1.Tumor-specificantigens(TSA)TSA:Antigensthatareonlyexpressedontumorcellsbutnotonnormalcells.highspecificity.

Tumorhigh-specificantigensTSA---onlyexpressedononekindoftumor,inducedbyphysiochemicalfactors,suchasX-rayTumorlow-specificantigensTSA---expressedonmorethanonekindoftumor,inducedbyvirusDiscoveryoftumorspecifictransplantationantigens,TSTA化學致癌劑甲基膽蒽(methyl-cholanthrene,MCA)

Tumorsexpressantigensthatarerecognizedasforeignbytheimmunesystemofthetumor-bearinghost.Immuneresponsefrequentlyfailtopreventthegrowthoftumors.Theimmunesystemcanbeactivatedbyexternalstimulatortoeffectivelykilltumorcellsanderadicatetumors.Conclusionfromthisexperiment2.Tumor-associatedantigens,TAAAntigensthatarealsoexpressedonnormalcells,buthighexpressedontumorcells.Withouttumorspecificity:CEA,AFPⅡ.CommonhumantumorantigensEmbryonicantigensTumorantigensinducedbyvirusesproteinscodedbyMutatedoncogeneorsuppressoroncogeneTATASexpressedonhumanmelanomacellsembryonicantigensareproteinsthatareexpressathighlevelsoncancercellsandinnormaldevelopingfetal,butpeteroutorverylowlevelinadult.Theirmainfunctionisthattheyprovidemarkersthataiddiagnosisoftumor.

Carcinoembryonicantigen(CEA)alpha-fetoprotein(AFP)1.embryonicantigensHighCEAlevelisnormallyrestrictedtocellsofthegut,pancreas,andliverinthecourseof2-6monthsofgestation,andlowlevelisfoundinserumofnormaladult(<5g/ml).CEAlevelofserumisincreasedinmanycarcinomas,suchasthecolon,pancreas,stomach,andbreast.ThelevelofserumCEAisusedtomonitorthepersistenceorrecurrenceofthetumorsaftertreatment.(1)Carcinoembryonicantigen(CEA)CEAlevelsinnormalindividualsarebelow2.5ng/ml,butitincreasessignificantlyincertainmalignancies,particularlycolo-rectalcancers.Itmayalsoriseinsomenonmalignantconditions(e.g.,chroniccirrhosis,pulmonaryemphysema,heavysmoking).Levels4-5-foldofnormalhavebeenusedtopredictrecurrenceofcolo-rectaltumors.Carcinoembryonicantigen:

clinicaluseAdjunctindiagnosisStagingandprognosisMonitoringresponsetotherapyDetectionoftumorrecurrenceCarcinoembryonicantigen:

clinicaluseAFPisacirculatingglycoproteinnormallysynthesizedandsecretedbytheyolksacandliveroffetal.SerumlevelsofAFPisverylowinserumofadult(≤20ng/ml),andtheconcentrationofAFPisupto500ng/mlinserumofpatientswithhepatocellularcarcinoma.higherriseinthisproteinisusedformonitoringhepatomasandtesticularcancers.AFPlevelmayalsoberaisedinsomenonmalignantconditions,suchascirrhosis,hepatitisandotherformsofliverdamage.(2)alpha-fetoprotein(AFP)Alphafetoprotein:concentrationsNormalconcentration:<20ng/mlAbnormalconcentrations100-350possiblehepatoma350-500probablehepatoma500-100likelyhepatoma>1000HEPATOMA2.Tumorantigensinducedbyviruses:HBV------livercancerHPV------cervicalcarcinomaEBV------Bcelllymphomaandnasopharyngealcarcinoma3.Productsofmutatedgenes:Sometumorantigensareproducedbymutatedgenes,suchassuppressoroncogenesp53andpro-oncogenerasSomepatientswithcancerhavecirculatingCD4+andCD8+TcellsthatcanrespondtotheproductsofmutatedgenessuchasRasandP53.Furthermore,inanimals,immunizationwithmutatedRasorP53proteinsinducesCTLsandrejectionresponsesagainsttumorsexpressingthesemutants.

Overexpressedcellularproteinsandabnormallyexpressedproteins:gp100,MAGEinmelanomasCancer-testisantigensPartⅡMechanismImmuneResponseTcells:αβT,γδTNKcellsCellularimmunityMacrophagesDendriticcellsHumoralimmunityⅠ.Cell-mediatedImmuneResponseTcellsNKcellsMacrophages(MΦ)Dendriticcells(DCs)1.Tlymphocytes:

TcellsTheprincipalmechanismoftumorimmunityiskillingoftumorcellsbyCTLTumorantigens

DCcrosspresentationCD8+T（CTL）CD4+Thcells(2)

TcellsNon-classⅠMHCrestrictionItstargetcellsarenothypersensitivetoNKcellsFirstlineofdefenceofimmunesurveillance2.NKcells:NKcellsarebroad-spectrumkillercellsItcankilltargetcellswithlowlevelornonMHCclassⅠmolecule.FirstlineofdefenceofimmunesurveillanceNK細胞識別MHCI類分子的受體

殺傷細胞免疫球蛋白樣受體(KIR)（MHC-G）KIR2DKIR3DKIR2DSKIR2DLKIR2DLKIR2DSDAP12ITAMITIM殺傷細胞凝集素樣受體（KLR）（HLA-E-9肽）CD94/NKG2A：ITIMCD94/NKG2C：連接DAP12-ITAMTumorcellactivated3.Macrophages(MΦ)①APC②releaseoflysosomalenzymes,reactiveoxygenintermediates,nitricoxide③ADCC④secretecytokines4.Dendriticcells:①

APC------Induceadaptiveimmuneresponse②InhibittumorgrowthdirectlyAntibodies:

①Activatingcomplement

②ADCC

③OpsonizationⅡ.HumoralimmuneresponsesAntitumorEffectorMechanismsCTLNKcellMacrophageHumoralMechanismsKumaretal.BasicPathology6thed.Figure6-32TumorcellFactorsrelatedtotumorcellsFactorsrelatedtothehost’simmunesystemPartⅢMechanismofTumorImmuneEscapeⅠ.Factorsrelatedtotumorcells1.lowimmunogenicityoftumorantigensandantigenicmodulation(1)lowimmunogenicityoftumorantigensThefailureofimmunosurveillancemaybethefactthatintheearlydevelopmentofatumor,theamountofantigenmaybetoosmalltostimulatetheimmunesystem.EscapefromimmunosurveillanceLackofNeo-antigens(2)antigenicmodulation:isaphenomenonthatcell-surfacetumorantigensaredecreaseorlosebecauseofattackofhost’shumoralimmune.2.coveringorblockingoftumorantigensonthesurfaceofthetumorcells3.DiminutionorabsenceofMHCclassImolecule4.Lackofco-stimulatorymoleculeonthesurfaceoftumorcells5.ImmuneinhibitorssecretedbytumorcellsEscapefromimmunosurveillanceⅡ.Factorsrelatedtohost’simmunesystem1.Immunodeficiency2.SuppressingimmunefunctionbytumordirectlyorindirectlyPartsⅣimmunotherapy

oftumorActiveimmunotherapyTargetimmunotherapyAdoptiveimmunotherapyCytokinetherapygenetherapyEscapefromimmunosurveillanceTumorsshedtheirneo-antigensFactorsrelatedtohost:PoorimmunefunctionTumorinhibitimmunefunctionofhostEscapefromimmunosurveillanceTumorssecreteImmunosuppressivemoleculesActiveimmunotherapyTargetimmunotherapyAdoptiveimmunotherapyCytokinetherapyGenetherapyPartⅤImmunotherapyoftumorsStimulationofactivehostimmuneresponsestotumors:Vaccinationwithtumorcellsandtumorantigens,orwithAPC.AugmentationofhostimmunitytotumorswithcytokinesandcostimulatorsNonspecificstimulationoftheimmunesystemVaccinationwithtumorcellsandtumorantigensDC:Use“primed”dendriticcells

APCscanbefedtumorantigensinthelaboratoryandtheninjectedintoapatient.TheinjectedcellsareprimedtoactivateTcellsAlternatively,DCscanbeinfectedwithaviralvector