肿瘤免疫学版课件.ppt

1、Tumor ImmunologyTumor ImmunologyYi Zhao Yi Zhao 赵赵 义义Dept.of Rheumatology Immunology,Xuanwu HospitalQuestions:o 你所认识的人中没有没因为肿瘤离你而去的？o 你对肿瘤的态度是什么？恨or绝望无耐or无所谓？o 你认为人类最终能战胜肿瘤吗？o 你猜测治疗肿瘤最有希望的方法将会是什么？Hepatocellular carcinomaCervical cancerLung cancerNasopharyngeal carcinomaLymphomaPancreatic carcinomaCa

2、ncer is the second leading cause of death in USA引自：引自：20082008年中国卫生事业统计公报年中国卫生事业统计公报知可以战与不可以战者胜，识众寡之用者胜，上下同欲者胜，以虞待不虞者胜，将能而君不御者胜。此五者，知胜之道也。孙子谋攻了解了解自身自身了解了解肿瘤肿瘤战胜战胜肿瘤肿瘤 Tumor immunology 肿瘤免疫学（肿瘤免疫学（tumor Immunology）:是是研究肿瘤的抗原性、机体的免疫功能与肿研究肿瘤的抗原性、机体的免疫功能与肿瘤发生、发展的相互关系，机体对肿瘤的瘤发生、发展的相互关系，机体对肿瘤的免疫应答及其抗肿瘤免疫的

3、机制、肿瘤的免疫应答及其抗肿瘤免疫的机制、肿瘤的免疫诊断和免疫防治的科学。免疫诊断和免疫防治的科学。Evidence for Tumor Immunityo The high frequency of cancers in immunosuppressed patientsnExtremes of age nPrimary and secondary immunodeficiencynImmunosuppressive drugso Tumors that are infiltrated by T cells have an improved prognosis o Spontaneous r

4、egression occurs nMelanoma,breast,lung cancersFThere may be tumor immunity,there was a high frequency of aberrant germs(tumor),which if not kept in check by the immune system,would overwhelm us.(1906)Paul EhrlichPaul EhrlichHallmarks免疫监视（免疫监视（Immunosurveillance）Burnett FMBurnett FMLewis ThomasLewis

5、Thomas1957年，Burnet和Thomas提出免疫监视学说,认为机体免疫系统通过细胞免疫机制能识别并特异地杀伤突变细胞，使突变细胞在未形成肿瘤之前即被清除，从而维持机体的稳态。人体的免疫系统具备一套精细的防止肿瘤抗原产生和肿瘤生长的机制，可分为三个阶段：1.清除 elimination2.相持 equilibrium 3.逃逸 escape免疫编辑免疫编辑（Immunoediting）Phases of Immunoediting:three Phases of Immunoediting:three“E E”s s肿瘤免疫学中的肿瘤免疫学中的“孙子兵法孙子兵法”免疫系统抗肿瘤机制肿瘤

6、逃逸肿瘤抗原肿瘤发生肿瘤的肿瘤的免疫学免疫学防治防治策略篇一、知彼篇一、知彼篇1.What is Tumor?肿瘤:是人体器官组织的细胞，在外来和内在有害因素的长期作用下所产生的一种以细胞过度增殖为主要特点的新生物(neoplasm)。Concepts o Tumor means a swelling or mass.A tumor can be benign(良性的)or malignant(恶性的).o Cancer(癌)refers to any malignant tumor.o Benign refers to a tumor which does not have the pote

7、ntial to spread beyond the organ it arises.o Malignant refers to a tumor which has the ability to spread or metastasize(转移)beyond the organ it arises.Features of cancer cells1.Escape normal intercellular communication2.Allow for rapid growth3.Increased mobility of cells4.Invade tissues5.Metastasis6.

8、Evade the immune system2.Etiology of tumor（1）External causesn Chemical agents(toxicant)n Physical agents(radiation)n Biologic agents(virus)（2）Internal causesn Gene(mutation)n Hormone(sexual hormone)n Immunity(immunodeficiency)Sex hormoneGeneImmunodeficiencyHow does a tumor form?研究表明，肿瘤细胞尽管来源于宿主细胞，但能

9、诱发机体产生免疫应答，这说明肿瘤细胞可能存在着与正常组织细胞不同的抗原成分，即肿瘤抗原。This is a fundamental issue for tumor immunology and its clinical applications.3.肿瘤抗原（Tumor antigens）Concepto Tumor antigens are:the antigenic molecules that newly-present or over-expressed in the neoplastic tissues or cells,which usually as the targets in

10、ducing the immune responses against the tumors.肿瘤抗原：肿瘤抗原：是泛指在肿瘤发生、发展过程中新出现或过是泛指在肿瘤发生、发展过程中新出现或过度表达的抗原物质，可被机体免疫系统识别，诱发抗肿度表达的抗原物质，可被机体免疫系统识别，诱发抗肿瘤免疫应答。对肿瘤抗原的研究是建立肿瘤免疫诊断和瘤免疫应答。对肿瘤抗原的研究是建立肿瘤免疫诊断和免疫治疗的基础。免疫治疗的基础。肿瘤抗原产生的分子机制 细胞癌变过程中合成的新的蛋白分子；由于基因突变或重排等使正常蛋白质分子的结构发生改变；由于糖基化等原因导致异常的细胞蛋白及其产物；正常情况下处于隐蔽状态的抗原表位

11、暴露出来；胚胎抗原、色素分化抗原或分化抗原的异常表达。不同机制产生的肿瘤抗原产生机制肿瘤抗原肿瘤致癌病毒产物人乳头瘤病毒E6和E7蛋白宫颈癌EB病毒核抗原1（EBNA-1）蛋白EBV相关淋巴瘤、鼻咽癌猿猴空泡病毒40（SV40）T抗原SV40诱导的啮齿类动物肿瘤基因突变或（抑）癌基因产物突变的p53蛋白约50%的人类肿瘤突变的Ras蛋白约10%的人类肿瘤过表达的HER-2/neu乳腺癌等糖基化蛋白神经节苷脂GM2和GD2黑色素瘤正常组织中的隐蔽抗原黑色素瘤抗原（MAGE-1、MAGE-3等）黑色素瘤等色素分化抗原Gp100、MART黑色素瘤胚胎抗原癌胚抗原（CEA）结肠癌等多种肿瘤甲胎蛋白（A

12、FP）肝癌分化抗原CD10、CD20B淋巴瘤前列腺特异抗原（PSA）前列腺癌Classification of tumor antigens发现和鉴定肿瘤抗原主要有两种途径:1.经典的免疫排斥实验2.免疫学和分子生物学相结合的方法，如通过肿瘤特异性T细胞或抗体鉴定肿瘤抗原并通过分子生物学技术克隆肿瘤抗原基因。根据其特异性和产生机制的不同，可将肿瘤抗原进行分类。（一）根据肿瘤抗原特异性分类1.肿瘤特异性抗原肿瘤特异性抗原 Tumor specific antigen(TSA)2.肿瘤相关抗原肿瘤相关抗原 Tumor associated antigen(TAA)1)Tumor-Specific

13、Antigen(TSA)TSA：是指肿瘤细胞特有的或只存在于某种肿瘤细胞而不存在于正常细胞的新抗原，又称为肿瘤特异性移植抗原或肿瘤排斥抗原。n早期移植排斥实验只能鉴定出抗原性较强的TSA，而后期发现这部分抗原实质上主要是肿瘤细胞来源的热休克蛋白（HSP）与肿瘤抗原多肽的复合物。n后期人们应用肿瘤特异性细胞毒性T细胞（CTL/Tc）结合分子生物学技术去发现肿瘤特异性抗原。n通过上述方法成功筛选出CTL识别的人黑色素瘤特异性抗原，如MAGE、BAGE、MART、gp100等。2)Tumor-Associated Antigens(TAA)TAA：是指肿瘤细胞和正常细胞组织均可表达的抗原，只是其含量

14、在细胞癌变时明显增高。此类抗原只表现出量的变化而无严格肿瘤特异性。胚胎抗原是其中的典型代表。Features of TSA and TAATumor antigenExpressing cellsSpeicficityAntigenicityOriginTSAtumor cellshighstrongPhysical and chemical agentsVirussilent genes or mutant cell genes Clonal antigenTAATumor cells normal cellslowweakMutant cell genesNormal cell genes

15、Oncofetal antigenDifferential antigen（二）根据肿瘤发生情况分类1.理化因素诱发：特异性高而抗原性弱，个体特异性明显，少见。如紫外线、X线暴露2.病毒诱发：抗原性较强而特异性较差，较为普遍。如EBV-淋巴瘤、鼻咽癌；HBV-肝癌等3.自发性肿瘤抗原：多类肿瘤为自发性，其抗原可类似于理化诱发或病毒诱发；与癌基因与抑癌基因的失活有关。如HER-2/neu与乳腺癌，Bcr/Ab1融合蛋白与慢性粒系白血病4.胚胎抗原或分化抗原 Raise monoclonal antibodieslUse antibodies for diagnosislUse antibodie

16、s for therapyStimulate the in vivo specific responseslSpecific active treatmentlSpecific passive treatmentlAdjuvant therapy to augment specific immunity（三）肿瘤抗原的用途 胚胎抗原是指在胚胎发育阶段由胚胎组织产生的正常成分，在胚胎后期减少，出生后逐渐消失，或仅存留极微量。但当细胞癌变时，此类抗原可重新合成而大量表达，又称为分化抗原。如PSA、黑色素瘤gp100和MART-1等。可分为两种：1.分泌性抗原：Alpha-fetoprotein(A

17、FP)2.肿瘤细胞膜表达抗原：Carcinoembryonic antigen(CEA)Embryonic antigenso High CEA level is normally restricted to cells of the gut,pancreas,and liver in the course of 2-6 months of gestation,and low level is found in serum of normal adult(5g/ml).o CEA level of serum is increased in many carcinomas,such as th

18、e colon,pancreas,stomach,and breast.o CEA levels in normal individuals are below 2.5 ng/ml,but it increases significantly in certain malignancies,particularly colorectal cancers.It may also rise in some nonmalignant conditions(e.g.,chronic cirrhosis,pulmonary emphysema,heavy smoking).Over 4-5-fold o

19、f normal levels can be used to predict recurrence of colorectal tumors.(1)Carcinoembryonic Antigen(CEA)CEA:clinical use1.Adjunct in diagnosis2.Staging and prognosis3.Monitoring response to therapy4.Detection of tumor recurrenceDegree of Expression is a Diagnostic ToolImmunohistochemistry-Cytology of

20、 ascites(fluid in abdomen)Stains positive for CEA-suggests the tumor is of colorectal origin(2)Alpha-fetoprotein(AFP)o AFP is a circulating glycoprotein normally synthesized and secreted by the yolk sac and liver of fetal.o Serum levels of AFP is very low in serum of adult(20ng/ml),and the concentra

21、tion of AFP is up to 500ng/ml in serum of patients with hepatocellular carcinoma.o Higher rise in this protein is used for monitoring hepatomas and testicular cancers.AFP level may also be raised in some nonmalignant conditions,such as cirrhosis,hepatitis and other forms of liver damage.Serum AFP Ca

22、n be Used for Screening and for Follow-uplMarkedly increased in most cases of hepatocellular carcinoma(HCC)lMay be slightly elevated in benign liver diseaselNormalizes with response to treatment,increases with recurrenceSerum AFP levels in a hepatitis B-positive Native Alaskan.He had a sudden increa

23、se in his AFP,which led to a diagnosis of HCC.The liver tumor was resected and AFP normalized.AFP(ng/mL)Time (years)HBsAg+HCC Resected4.肿瘤的免疫逃逸机制o 肿瘤抗原能够诱导机体免疫系统产生免疫应答，但为何很多肿瘤仍能在机体内进行性生长，并导致宿主死亡？o 肿瘤的生长涉及到诸多方面，如肿瘤细胞特性、肿瘤细胞周围微环境及宿主免疫系统等多方面。（1）肿瘤细胞的抗原缺失和抗原调变o Lack of tumor antigenso Antigenic modulati

24、on:is a phenomenon that cell-surface tumor antigens are decrease or lose because of attack of hosts humoral immune.（2）肿瘤细胞MHC I类分子表达缺陷或低下或缺乏共刺激信号Induction of T Lymphocyte AnergyCD8+TCTumor CellAnergyMHC Class ICD8+TCTumor CellTc ActivationB7CD28(Co-stimulation)（3）肿瘤细胞的凋亡抵抗作用o 高表达多种抗凋亡分子（如Bcl-2），不表达或

25、弱表达Fas等凋亡诱导分子，从而抵抗凋亡的诱导，逃避CTL的杀伤效应。（4）肿瘤细胞的“逃逸”o 由于肿瘤细胞的迅速生长超越了机体抗肿瘤免疫效应的限度，致使宿主不能有效地清除大量生长的肿瘤细胞。（5）肿瘤细胞导致的免疫抑制Inhibiting cytokines:TGFIL-10T CellTumor CellApoptosisFasL+Other Molecules that Induce ApoptosisFas+Other“Death Receptors”6.宿主方面的免疫抑制或缺陷o Hosts receiving the treatment of immunosuppressants

26、(e.g.corticosteroid,cytotoxic drugs)o immunodeficiency disease(e.g.HIV infection)二、知己篇What is our bodys firewall?Startup the firewallOur immune systemImmune organsImmune cellsImmune moleculesCancersImmunityvsDeath vs Life1.Cell-mediated immunity innate immunity adaptive immunity2.Humoral immunity An

27、tibody-mediated immunity Anti-tumor cytokinesInnate immunityo Natural killer(NK)o Mononuclear macrophageo TCR+T cell o Neutrophil Natural Killer CellsDo not recognize tumor cell via antigen specific cell surface receptor,but through receptors that recognize loss of expression of MHC I molecules,ther

28、efore detect“missing self”common in cancer.1.Lyze the tumor cells by secreting the perforin and granzyme;2.Inducing the apoptosis of tumor through the interaction of FasL and Fas;3.Secreting the cytokines to kill tumor cells4.Antibody dependent cell mediated cytotoxicity.Anti-tumor effect of NK cell

29、sTumor cellactivatedMononuclear macrophageo Macrophage mediated tumor cytotoxicity;o Antibody dependent cell mediated cytotoxicity;o Complement dependent cytotoxicity;o Anti-tumor cytokines(TNF,IL-12).TCR+T cello They are a minor group of T cells with sort of NK-like features.Its target cells are no

30、t hypersensitive to NK cells.o Killing tumor with MHC restriction or non-MHC restriction(usually)o Secreting perforin and granzymeo Anti-tumor cytokines(IL-2,4,5,IFN,TNF)Adaptive immunityT cell responses:T lymphocytes play a key role in the anti-tumor immune reponses.The principal mechanism of tumor

31、 immunity is killing of tumor cells by cytotoxic T cells(CTL).The host can produce multiple antibodies against tumor antigens,but not all of these antibodies will be benefit to prevent the host from tumors.Antibody dependent cell mediated cytotoxicity Complement dependent antibody mediated cytotoxic

32、ity Antibody mediated phagocytolysis Deblocking factor effect Specific antibodies targeting tumor antigensAntibody-mediated immunityAnti-tumor cytokines o Interleukin(ILs)nEnhance the effects of T cell,macrophages,NK cells and B cellso Interferon(IFN、)nInhibit the proliferation of tumor viruses and

33、mitosis of tumor cellso Tumor necrosis factor(TNF)nDirect or indirect cytotoxicity upon tumor cellso colony-stimulating factor(CSF)nImmunomodulation三、策略篇1.肿瘤的免疫预防o 提高机体免疫系统功能：饮食、运动、生活方式；o 制备肿瘤相关病原体疫苗：HPV疫苗应用于宫颈癌预防2.肿瘤的治疗oSurgeryoRadiotherapyoChemotherapyoImmunotherapy:aims to:enhance the immunity of

34、 host to kill tumor cells with high specificity and low side-effect.We usually combine above four methods to fight against tumors.3.肿瘤的免疫治疗o 非特异性免疫治疗o 特异性免疫治疗n 主动免疫治疗n 过继免疫治疗1)非特异性免疫治疗非特异性免疫治疗o 免疫调节剂:非特异性增强宿主的免疫功能、激活宿主的抗肿瘤免疫应答。n BCG,OK432，CpG-DNA/ODNo 细胞因子：n Interleukin,interferon,TNFBacillus Calmet

35、te-Guerin(BCG)p 可通过激活的T辅助细胞所产生的IL-2及IFN-等激活体内的巨噬细胞及NK细胞或直接激活巨噬细胞，增强其杀伤活性。另外，BCG可做为免疫佐剂增强其他抗肿瘤药物的治疗效果。p 毒副作用较大。OK432o 来源为溶血性链球菌A级三型低毒变异株o 能增强效应细胞的杀瘤功能o 对肿瘤细胞具有直接杀伤作用o 毒副作用小CpG-DNA/ODNo 作用于机体抗原提呈细胞，刺激抗原提呈细胞分泌IL-12和TNF-，上调与抗原提呈相关的MHC分子、共刺激分子等，刺激T细胞和NK细胞产生IFN-。o 作用明显、制备简便。Cytokines used as adjuvants for

36、 immunotherapyCytokinesActivityIL-2helper signal for CD8+T cells,bypassing T help cellenhances the activity of some NK clonesIL-4Promotes maturation and enhances APC functionIL-12With IL-2 to induce differentiation of CD8+cells GM-CSFUp-regulates expression of MHC-I and MHCII and costimulator molecu

37、lesIFN-Activates macrophages,NK cells and B cellsinduces differentiation of B cells 2)特异性免疫治疗o 主动免疫治疗：利用肿瘤抗原的免疫原性，采用有效的免疫手段使宿主免疫系统产生针对肿瘤抗原的抗肿瘤免疫应答。o 被动免疫治疗：给机体输注外源性的免疫效应物质包括抗体、细胞因子、免疫效应细胞等，由这些外源性的免疫效应物质在宿主体内发挥抗肿瘤作用。主动免疫治疗瘤苗 活瘤苗：来源自体或同种活的瘤细胞，具有一定危险性。减毒或灭活瘤苗：肿瘤细胞经照射、化疗或高低温处理。异构瘤苗：经化学修饰或病毒感染等处理后，以增强其免疫

38、原性。基因修饰瘤苗：转入细胞因子基因、辅助刺激分子基因、MHC等基因。抗独特型抗体瘤苗：分子瘤苗：核酸疫苗或DNA疫苗 抗原提呈细胞为基础的瘤苗被动免疫治疗o 抗体的导向治疗：人类表皮生长因子受体-2（HER-2）基因工程抗体用于治疗乳腺癌；针对CD20的基因工程抗体用于B细胞淋巴瘤；针对EGFR的基因工程抗体用于转移性结直肠癌。o 细胞因子输注疗法：IFN-、IFN-、G-CSF、GM-CSF。o 过继免疫治疗：将活化的免疫活性细胞转输给肿瘤患者，为其提供现成的免疫力，如LAK，TIL或单核巨噬细胞等。本章要点本章要点1.概念：肿瘤、肿瘤免疫学、肿瘤抗原（TSA和TAA）；2.肿瘤抗原的分类以及常见肿瘤抗原的临床意义；3.机体抗肿瘤免疫机制；4.肿瘤逃逸机制；5.主要的肿瘤免疫治疗方法。