肿瘤学-肿瘤与免疫

儿科学

第一章绪论复旦大学附属儿科医院桂永浩肿瘤学

第十章肿瘤与免疫

Prof.ZhigangTianInstituteofImmunologyUniversityofScienceandTechnologyofChina肿瘤免疫TumorImmunologyToleranceImmunityToleranceImmunityInnateimmunityAdaptiveimmunityTumorImmunologyTumorImmunology是研究肿瘤抗原地种类与质,机体对肿瘤地免疫效应机制以与肿瘤地免疫逃逸方式与机制,肿瘤地免疫诊断与免疫治疗地科学一.TumorRejectionAntigens二.Cancerimmunosurveillance三.MechanismsofTumorEscape四.cancer-relatedinflammation五.ImmunotherapyofTumorsUsingtheImmuneResponsetoAttackTumors

一.TumorRejectionAntigens

TumorrejectionantigensarespecifictoindividualtumorsTRA:TumorRejectionAntigensTRAsarepeptidesofmutantoroverexpressedcellularproteinsboundtoMHCclassImoleculesonthetumorcellsurface特点一.Tumor-specificantigens二.selectivelyexpressedinhumantumors三.CanberecognitionbyTcells四.mountaprotectiveimmuneresponseagainsttumorsTumorrejectionantigensarespecifictoindividualtumors类TSA地分类（一）病毒癌基因编码地抗原病毒癌基因编码地抗原,这些致癌病毒蛋白在瘤形成过程起重要作用,由于是外源地,可以引起TC应答（二）突变基因编码地抗原突变基因编码地抗原,其与野生型基因产物地差别仅为一个或数个氨基酸残基,但由此形成新地表位或导致与MHC分子结合地亲与力发生改变,从而成为新地抗原类TSA地分类Tumorrejectionantigensmayarisebypointmutationsinselfproteins,whichoccurduringtheprocessofoncogenesis类TSA地分类（三）静止基因异常活化后编码地蛋白(Cancer-testisantigen)正常状态下地静止基因,通常只表达于男胚系细胞,不表达MHC分子,不能提呈肽给TC。肿瘤细胞异常广泛地表达,其编码蛋白可被机体免疫细胞所识别类TSA地分类Tumor-associatedantigensarenonspecifictotumorsTAA:Tumor-associatedantigens肿瘤细胞与正常组织细胞均可表达,但是含量在细胞癌变时显著增高地抗原。又称为同肿瘤抗原（sharedtumorantigen）Tumor-associatedantigensarenonspecifictotumors特点一.TAA难以刺激机体产生细胞免疫应答,但可被B细胞识别并产生相应地抗体二.TAA在肿瘤地临床实践具有很重要地作用:肿瘤早期诊断地辅助指标与靶向治疗地靶点,疗效地评估,复发转移与预后地判断类TAA地分类（一）组织特异分化抗原组织特异分化抗原高表达于特定组织肿瘤,但相应正常组织仅低表达,在其它正常组织或其它肿瘤则不表达（二）过量表达地抗原过量表达地抗原打破了机体自身耐受而诱发免疫应答（肿瘤组织高表达,正常组织低表达）类TAA地分类（三）表现为异常翻译,转录后修饰地蛋白异常翻译,转录后修饰地蛋白,如粘蛋白,在癌组织表达出现异常,如糖基化不完全,缺失,突变以与出现相应正常组织不表达地粘蛋白类型。这类抗原可诱发BC产生抗体与激发CTL反应类TAA地分类（四）胚胎抗原当细胞恶变时,相应编码基因可被激活呈异常表达。胚胎抗原在宿主体内难以激发抗肿瘤免疫应答。可作为肿瘤地临床诊断,复发与预后判断地辅助指标甲胎蛋白（alpha-fetoprotein,AFP）癌胚抗原（carcinoembryonicantigen,CEA）类TAA地分类二.Cancerimmunosurveillance

免疫监视地证据淋巴细胞在肿瘤组织地浸润IFN-抑制肿瘤组织内血管地形成TRAAPCCD四TCD八TBNKCTL穿孔素/粒酶Fas/FasL淋巴毒素,TNFMIL-二IFN-TNF-机体免疫系统所有组分,特异地与非特异地,体液与细胞免疫影响肿瘤地发生与发展EffectorMechanismsAgainstTumorsEffectorMechanismsAgainstTumorsbyTCAPCCD四+CTLTh一CytotoxicityThCTLThTcActivationTRAYYYYYYYPCYYYBCTh二EffectorMechanismsAgainstTumorsbyNKcell受体介导地NK细胞杀伤补体成分＋CDCFcRNKMPhagocytosisADCC抗体封闭干扰粘附EffectorMechanismsAgainstTumorsbyPCUsingtheImmuneResponsetoAttackTumors三.MechanismsofTumorEscape

TumorImmunoeditingEliminationImmunesystemTumorEquilibriumEscapeImmunesurveillanceImmuneselectionImmunesubversionPre-malignantlesionAdvancedoncogenesisTumorgrowthImmunoeselection-destructionofcancercellswithhighimmunogenicityRetentionofcancercellswithlowimmunogenicity-aselectiveprocessMalignantcellscanbecontrolledbyimmunesurveillanceImmunesurveillanceImmuneselectionImmunesubversionPre-malignantlesionEliminationEquilibriumEscapeAdvancedoncogenesisTumorgrowthTumorImmunoeditingMechanismsbywhichtumorsavoidimmunerecognition一.Lowimmunogenicity（一）Nopeptide:MHCligand（二）Noadhensionmolecules（三）Noco-stimulatorymoleculesTCD八CD二八TCRLFA-一二.TumortreatedasselfantigenTumorantigenstakeupandpresentedbyAPCsinabsenceofco-stimulationtolerizeTcellsTH一CTLanergyMechanismsbywhichtumorsavoidimmunerecognition三.Antigenicmodulation（一）Antibodyagainsttumorcell-surfaceantigenscaninduceendocytosisanddegradationoftheantigen（二）Immuneselectionofantigenlossvariants是利用肿瘤特异抗体行免疫治疗所面临地主要问题之一Mechanismsbywhichtumorsavoidimmunerecognition四.Tumor-inducedimmunesuppression（一）Factors(e.g.,TGF,IL-一零)secretedbytumorcellsinhibitTcellsdirectly（二）InductionofregulatoryTcellsbytumorsCTLTH一TGF-TregTGF--TGF-IL-一零+---Mechanismsbywhichtumorsavoidimmunerecognition四.Tumor-inducedimmunesuppression（三）Factors(e.g.,IDO))secretedbytumorcellsinhibitTcellsdirectlyCTLTH一IDOTreg---IDO:吲哚胺二,三双加氧酶（indoleamine二,三,-dioxygenase）是哺乳动物肝外组织色氨酸代谢地限速酶。肿瘤细胞在IFN作用下可产生IDO,使得其所处地微环境出现"色氨酸饥饿",抑制T细胞增殖,同时色氨酸代谢产物对T细胞也存在细胞毒作用Mechanismsbywhichtumorsavoidimmunerecognition四.Tumor-inducedimmunesuppression（四）TumordirectinhibitimmuneresponseCTLPD-L一-Mechanismsbywhichtumorsavoidimmunerecognition五.Tumor-inducedprivilegedsiteFactorssecretedbytumorcellscreateaphysicalbarriertotheimmunesystemTH一CTLMechanismsbywhichtumorsavoidimmunerecognitionLossofMHCclassIexpressioninaprostaticcarcinomaMechanismsbywhichtumorsavoidimmunerecognitionMechanismsbywhichtumorsavoidimmunerecognitionTumorsthatloseexpressionofallMHCclassImoleculesasamechanismofescapefromimmunesurveillancearemoresusceptibletoNKcellkilling六零minutesaftermixingshortlyaftermixingNK细胞白血病细胞Mechanismsbywhichtumorsavoidimmunerecognition四.cancer-relatedinflammation

cancer-relatedinflammationcancer-relatedinflammation肿瘤有关炎症是恶肿瘤地第七大生物学特征cancer-relatedinflammationImmunoscoreImmunoscore免疫学评分（Immunoscore）基于两类不同地淋巴细胞群——记忆T细胞与杀伤T细胞（CD三+CD四五RO+与CD三+CD八+或CD八+CD四五RO+细胞）在CT与IM区地富集程度。利用免疫组织化学染色,通过数字病理学软件对结果行分析评判,根据Immunoscore"I"零-"I"四级地评分系统行评分五.ImmunotherapyofTumors

ImmunotherapyofTumorsTwogeneralapproachesPassiveimmunizationMonoclonalAntibodiesActiveimmunizationStimulateendogenousimmunesystem（一）Tumorvaccine（二）GeneTherapyImmunotherapyofTumorsTwogeneralapproachesPassiveimmunizationMonoclonalAntibodiesActiveimmunizationStimulateendogenousimmunesystem（一）Tumorvaccine（二）GeneTherapyMonoclonalAntibodiesMechanismADCCEnhancedplementactivationOpsonizationLysisviaMACChemotaxisMonoclonalAntibodiesMechanismReceptorblockageReducedsignalingTargetingoftoxicsubstancesToxonsRadioactivepoundsPro-drugconvertingenzymesUn-conjugatedMoAb一.ADCC二.Herceptin三.anti-CD二零Antibody-coatedtumorcellscanbekilledbyNKcellsinantibody-dependentcell-mediatedcytotoxicity(ADCC)TumorTumorNKTumorTumorNKFcgRIII(CD一六)Tumor-specificantibodiesofthecorrectisotypesmightbeabletodirectthelysisofthetumorcellsbyNKcells,activatingtheNKcellsviatheirFcreceptorsNKcellkillingPerforinGranzymesUn-conjugatedMoAbtreatmentofbreastcancerwithHerceptinHerceptinhumanizedmonoclonalantibodytargetsreceptorHER-二/neuHER-二/neuoverexpressedinaboutaquarterofbreastcancerpatientsHerceptin(trastuzumab)breastcancerBlockinginteractionbetweenthereceptoranditsligandDownregulatingthelevelofexpressionofthereceptorTheeffectscanbepotentiatedwhenitisbinedwithconventionalchemotherapyUn-conjugatedMoAbTreatmentofnon-Hodgkin'sB-celllymphomawithAnti-CD二零McAbCD二零non-Hodgkin'sB-celllymphomaRituximaivLigationandclusteringofCD二零Un-conjugatedMoAb但肿瘤细胞常常发生突变,结果不再与治疗抗体结合,这种遗传地不稳定使肿瘤逃避抗体地免疫治疗治疗好转Un-conjugatedMoAbConjugatedMoAb一.ImmunotoxinRicinA（蓖麻毒素A）Pseudomonas（细菌假单胞菌毒素）二.Chemotherapeuticdrugs三.radioisotopesImmunotoxin:单抗与蛋白质毒素之类生物制剂地联物称为免疫毒素Antibody-DirectedEnzyme/Pro-drugTherapy(ADEPT)Ab-enzymePro-drugActivedrug抗体导向酶解前药治疗ConjugatedMoAbAntibody-DirectedisotopyTherapyAb-isotopyConjugatedMoAbTumordiagnosisMcAbcoupledtoγ-emittingradioisotopeshavealsobeenuseddiagnosisandmonitoringtumorspreadivMcAb-radioisotopes结直肠癌肺癌卵巢癌前列腺癌ConjugatedMoAbTumordiagnosis体内肿瘤地放射免疫成像诊断肺癌ConjugatedMoAbTumordiagnosisRecurrentcolorectalcancercanbedetectedwitharadiolabe