肿瘤免疫学-2013版七年制

Tumor Immunology,Yi Zhao 赵 义Dept. of Rheumatology Immunology, Xuanwu Hospital,Questions:,你所认识的人中没有没因为肿瘤离你而去的？你对肿瘤的态度是什么？恨or绝望无耐or无所谓？你认为人类最终能战胜肿瘤吗？你猜测治疗肿瘤最有希望的方法将会是什么？,肿瘤就在我们身边！,Cancer is the second leading cause of death in USA,引自：2008年中国卫生事业统计公报,顶尖杀手,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,Tumor immunology,肿瘤免疫学（tumor Immunology）:是研究肿瘤的抗原性、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。,Evidence for Tumor Immunity,The high frequency of cancers in immunosuppressed patientsExtremes of age Primary and secondary immunodeficiencyImmunosuppressive drugsTumors that are infiltrated by T cells have an improved prognosis Spontaneous regression occurs Melanoma, breast, lung cancers,There 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 Ehrlich,Hallmarks,免疫监视（Immunosurveillance）,Burnett FM,Lewis Thomas,1957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（Immunoediting）,Phases of Immunoediting: three “E”s,肿瘤免疫学中的“孙子兵法”,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,Tumor means a swelling or mass. A tumor can be benign (良性的) or malignant (恶性的).Cancer (癌) refers to any malignant tumor. Benign refers to a tumor which does not have the potential to spread beyond the organ it arises.Malignant refers to a tumor which has the ability to spread or metastasize (转移) beyond the organ it arises.,Features of cancer cells,Escape normal intercellular communicationAllow for rapid growthIncreased mobility of cellsInvade tissuesMetastasisEvade the immune system,2.Etiology of tumor,（1）External causesChemical agents (toxicant)Physical agents (radiation)Biologic agents (virus),（2）Internal causesGene (mutation)Hormone (sexual hormone)Immunity (immunodeficiency),Sex hormone,Gene,Immunodeficiency,How does a tumor form?,研究表明，肿瘤细胞尽管来源于宿主细胞，但能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）,Concept,Tumor antigens are: the antigenic molecules that newly-present or over-expressed in the neoplastic tissues or cells, which usually as the targets inducing the immune responses against the tumors. 肿瘤抗原：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。,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,Classification of tumor antigens,发现和鉴定肿瘤抗原主要有两种途径:经典的免疫排斥实验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,肿瘤特异性抗原 Tumor specific antigen (TSA) 肿瘤相关抗原 Tumor associated antigen (TAA),1) Tumor-Specific 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。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。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。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 TAA,（二）根据肿瘤发生情况分类,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胚胎抗原或分化抗原,Raise monoclonal antibodiesUse antibodies for diagnosisUse antibodies for therapyStimulate the in vivo specific responsesSpecific active treatmentSpecific passive treatmentAdjuvant 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：分泌性抗原：Alpha-fetoprotein (AFP)肿瘤细胞膜表达抗原：Carcinoembryonic antigen (CEA),Embryonic antigens,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).CEA level of serum is increased in many carcinomas ,such as the colon, pancreas, stomach, and breast.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 of normal levels can be used to predict recurrence of colorectal tumors.,(1) Carcinoembryonic Antigen (CEA),CEA: clinical use,Adjunct in diagnosisStaging and prognosisMonitoring response to therapyDetection of tumor recurrence,Degree of Expression is a Diagnostic Tool,Immunohistochemistry - Cytology of ascites (fluid in abdomen)Stains positive for CEA - suggests the tumor is of colorectal origin,(2) Alpha-fetoprotein (AFP),AFP is a circulating glycoprotein normally synthesized and secreted by the yolk sac and liver of fetal.Serum levels of AFP is very low in serum of adult (20ng/ml), and the concentration of AFP is up to 500ng/ml in serum of patients with hepatocellular carcinoma. 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 Can be Used for Screening and for Follow-up,Markedly increased in most cases of hepatocellular carcinoma (HCC)May be slightly elevated in benign liver diseaseNormalizes with response to treatment, increases with recurrence,Serum AFP levels in a hepatitis B-positive Native Alaskan. He had a sudden increase in his AFP, which led to a diagnosis of HCC. The liver tumor was resected and AFP normalized.,4. 肿瘤的免疫逃逸机制,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？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,Lack of tumor antigensAntigenic modulation: 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 Anergy,（3）肿瘤细胞的凋亡抵抗作用,高表达多种抗凋亡分子（如Bcl-2），不表达或弱表达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”,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-10,6. 宿主方面的免疫抑制或缺陷,Hosts receiving the treatment of immunosuppressants (e.g. corticosteroid, cytotoxic drugs) immunodeficiency disease (e.g. HIV infection),二、知己篇,What is our bodys firewall?,Startup the firewall,Immune system,Our immune system,Immune organs,Immune cells,Immune molecules,Cancers,Immunity,vs,Death vs Life,魔高一尺，道高一丈,What role does immune system playsas a tumor occurs in our body?,Cell-mediated immunity innate immunityadaptive immunityHumoral immunityAntibody-mediated immunityAnti-tumor cytokines,免疫系统抗肿瘤机制,Innate immunity,Natural killer (NK)Mononuclear macrophageTCR+ T cell Neutrophil,Natural Killer Cells,Do not recognize tumor cell via antigen specific cell surface receptor, but through receptors that recognize loss of expression of MHC I molecules, therefore detect “missing self” common in cancer.,Lyze the tumor cells by secreting the perforin and granzyme;Inducing the apoptosis of tumor through the interaction of FasL and Fas; Secreting the cytokines to kill tumor cellsAntibody dependent cell mediated cytotoxicity.,Anti-tumor effect of NK cells,Tumor cell,activated,Mononuclear macrophage,Macrophage mediated tumor cytotoxicity;Antibody dependent cell mediated cytotoxicity;Complement dependent cytotoxicity;Anti-tumor cytokines (TNF, IL-12).,TCR+ T cell,They are a minor group of T cells with sort of NK-like features. Its target cells are not hypersensitive to NK cells.Killing tumor with MHC restriction or non-MHC restriction (usually)Secreting perforin and granzymeAnti-tumor cytokines (IL-2,4,5,IFN,TNF),Adaptive immunity,T cell responses: T lymphocytes play a key role in the anti-tumor immune reponses.The principal mechanism of tumor 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 cytotoxicityComplement dependent antibody mediated cytotoxicityAntibody mediated phagocytolysisDeblocking factor effectSpecific antibodies targeting tumor antigens,Antibody-mediated immunity,Anti-tumor cytokines,Interleukin (ILs)Enhance the effects of T cell, macrophages, NK cells and B cellsInterferon (IFN、)Inhibit the proliferation of tumor viruses and mitosis of tumor cellsTumor necrosis factor (TNF)Direct or indirect cytotoxicity upon tumor cellscolony-stimulating factor (CSF)Immunomodulation,三、策略篇,1. 肿瘤的免疫预防,提高机体免疫系统功能：饮食、运动、生活方式； 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,SurgeryRadiotherapyChemotherapyImmunotherapy: aims to: enhance the immunity of 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,非特异性免疫治疗特异性免疫治疗主动免疫治疗过继免疫治疗,1) 非特异性免疫治疗,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。BCG, OK432，CpG-DNA/ODN细胞因子：Interleukin, interferon, TNF,Bacillus Calmette-Guerin (BCG),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。毒副作用较大。,OK432,来源为溶血性链球菌A级三型低毒变异株能增强效应细胞的杀瘤功能对肿瘤细胞具有直接杀伤作用毒副作用小,CpG-DNA/ODN,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