腫瘤抗原的分類、免疫機(jī)制和治療方法（英文版）

1、腫瘤抗原的分類、免疫機(jī)制和治療方法（英文版）Questions:你所認(rèn)識(shí)的人中沒有沒因?yàn)槟[瘤離你而去的？你對(duì)腫瘤的態(tài)度是什么？恨or絕望無耐or無所謂？你認(rèn)為人類最終能戰(zhàn)勝腫瘤嗎？你猜測(cè)治療腫瘤最有希望的方法將會(huì)是什么？Hepatocellular carcinomaCervical cancerLung cancerNasopharyngeal carcinomaLymphomaPancreatic carcinoma腫瘤就在我們身邊！Cancer is the second leading cause of death in USA引自：2008年中國衛(wèi)生事業(yè)統(tǒng)計(jì)公報(bào)頂尖殺手知可以戰(zhàn)與不可

2、以戰(zhàn)者勝，識(shí)眾寡之用者勝，上下同欲者勝，以虞待不虞者勝，將能而君不御者勝。此五者，知?jiǎng)僦酪?。孫子謀攻了解自身了解腫瘤戰(zhàn)勝腫瘤 Tumor immunology 腫瘤免疫學(xué)（tumor Immunology）:是研究腫瘤的抗原性、機(jī)體的免疫功能與腫瘤發(fā)生、發(fā)展的相互關(guān)系，機(jī)體對(duì)腫瘤的免疫應(yīng)答及其抗腫瘤免疫的機(jī)制、腫瘤的免疫診斷和免疫防治的科學(xué)。Evidence for Tumor ImmunityThe high frequency of cancers in immunosuppressed patientsExtremes of age Primary and secondary immu

3、nodeficiencyImmunosuppressive drugsTumors that are infiltrated by T cells have an improved prognosis Spontaneous regression occurs Melanoma, breast, lung cancersThere may be tumor immunity, there was a high frequency of aberrant germs(tumor), which if not kept in check by the immune system, would ov

4、erwhelm us. (1906)Paul EhrlichHallmarks免疫監(jiān)視（Immunosurveillance）Burnett FMLewis Thomas1957年，Burnet和Thomas提出免疫監(jiān)視學(xué)說,認(rèn)為機(jī)體免疫系統(tǒng)通過細(xì)胞免疫機(jī)制能識(shí)別并特異地殺傷突變細(xì)胞，使突變細(xì)胞在未形成腫瘤之前即被清除，從而維持機(jī)體的穩(wěn)態(tài)。 人體的免疫系統(tǒng)具備一套精細(xì)的防止腫瘤抗原產(chǎn)生和腫瘤生長的機(jī)制，可分為三個(gè)階段：1.清除 elimination2. 相持 equilibrium 3. 逃逸 escape免疫編輯（Immunoediting）Phases of Immunoediting:

5、 three “E”s腫瘤免疫學(xué)中的“孫子兵法”免疫系統(tǒng)抗腫瘤機(jī)制腫瘤逃逸腫瘤抗原腫瘤發(fā)生腫瘤的免疫學(xué)防治策略篇一、知彼篇1.What is Tumor?腫瘤: 是人體器官組織的細(xì)胞，在外來和內(nèi)在有害因素的長期作用下所產(chǎn)生的一種以細(xì)胞過度增殖為主要特點(diǎn)的新生物 (neoplasm)。Concepts Tumor means a swelling or mass. A tumor can be benign (良性的) or malignant (惡性的).Cancer (癌) refers to any malignant tumor. Benign refers to a tumor whi

6、ch 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 (轉(zhuǎn)移) beyond the organ it arises. Features of cancer cellsEscape normal intercellular communicationAllow for rapid growthIncreased mobility of cellsInvade tis

7、suesMetastasisEvade the immune system2.Etiology of tumor（1）External causesChemical agents (toxicant)Physical agents (radiation)Biologic agents (virus)（2）Internal causesGene (mutation)Hormone (sexual hormone)Immunity (immunodeficiency)Sex hormoneGeneImmunodeficiency研究表明，腫瘤細(xì)胞盡管來源于宿主細(xì)胞，但能誘發(fā)機(jī)體產(chǎn)生免疫應(yīng)答，這說明

8、腫瘤細(xì)胞可能存在著與正常組織細(xì)胞不同的抗原成分，即腫瘤抗原。This is a fundamental issue for tumor immunology and its clinical applications. 3. 腫瘤抗原（Tumor antigens）ConceptTumor antigens are: the antigenic molecules that newly-present or over-expressed in the neoplastic tissues or cells, which usually as the targets inducing the i

9、mmune responses against the tumors. 腫瘤抗原：是泛指在腫瘤發(fā)生、發(fā)展過程中新出現(xiàn)或過度表達(dá)的抗原物質(zhì)，可被機(jī)體免疫系統(tǒng)識(shí)別，誘發(fā)抗腫瘤免疫應(yīng)答。對(duì)腫瘤抗原的研究是建立腫瘤免疫診斷和免疫治療的基礎(chǔ)。腫瘤抗原產(chǎn)生的分子機(jī)制細(xì)胞癌變過程中合成的新的蛋白分子；由于基因突變或重排等使正常蛋白質(zhì)分子的結(jié)構(gòu)發(fā)生改變； 由于糖基化等原因?qū)е庐惓５募?xì)胞蛋白及其產(chǎn)物； 正常情況下處于隱蔽狀態(tài)的抗原表位暴露出來； 胚胎抗原、色素分化抗原或分化抗原的異常表達(dá)。不同機(jī)制產(chǎn)生的腫瘤抗原產(chǎn)生機(jī)制腫瘤抗原腫瘤致癌病毒產(chǎn)物人乳頭瘤病毒E6和E7蛋白宮頸癌EB病毒核抗原1（EBNA-1）蛋白E

10、BV相關(guān)淋巴瘤、鼻咽癌猿猴空泡病毒40（SV40）T抗原SV40誘導(dǎo)的嚙齒類動(dòng)物腫瘤基因突變或（抑）癌基因產(chǎn)物突變的p53蛋白約50%的人類腫瘤突變的Ras蛋白約10%的人類腫瘤過表達(dá)的HER-2/neu乳腺癌等糖基化蛋白神經(jīng)節(jié)苷脂GM2和GD2黑色素瘤正常組織中的隱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）結(jié)腸癌等多種腫瘤甲胎蛋白（AFP）肝癌分化抗原CD10、CD20B淋巴瘤前列腺特異抗原（PSA）前列腺癌Classification of tumor antigens發(fā)現(xiàn)和鑒定腫瘤抗原主要有兩種途徑:經(jīng)典

11、的免疫排斥實(shí)驗(yàn)免疫學(xué)和分子生物學(xué)相結(jié)合的方法，如通過腫瘤特異性T細(xì)胞或抗體鑒定腫瘤抗原并通過分子生物學(xué)技術(shù)克隆腫瘤抗原基因。根據(jù)其特異性和產(chǎn)生機(jī)制的不同，可將腫瘤抗原進(jìn)行分類。（一）根據(jù)腫瘤抗原特異性分類腫瘤特異性抗原 Tumor specific antigen (TSA) 腫瘤相關(guān)抗原 Tumor associated antigen (TAA)1) Tumor-Specific Antigen (TSA)TSA：是指腫瘤細(xì)胞特有的或只存在于某種腫瘤細(xì)胞而不存在于正常細(xì)胞的新抗原，又稱為腫瘤特異性移植抗原或腫瘤排斥抗原。早期移植排斥實(shí)驗(yàn)只能鑒定出抗原性較強(qiáng)的TSA，而后期發(fā)現(xiàn)這部分抗原實(shí)質(zhì)

12、上主要是腫瘤細(xì)胞來源的熱休克蛋白（HSP）與腫瘤抗原多肽的復(fù)合物。后期人們應(yīng)用腫瘤特異性細(xì)胞毒性T細(xì)胞（CTL/Tc）結(jié)合分子生物學(xué)技術(shù)去發(fā)現(xiàn)腫瘤特異性抗原。通過上述方法成功篩選出CTL識(shí)別的人黑色素瘤特異性抗原，如MAGE、BAGE、MART、gp100等。2) Tumor-Associated Antigens (TAA)TAA：是指腫瘤細(xì)胞和正常細(xì)胞組織均可表達(dá)的抗原，只是其含量在細(xì)胞癌變時(shí)明顯增高。此類抗原只表現(xiàn)出量的變化而無嚴(yán)格腫瘤特異性。胚胎抗原是其中的典型代表。Features of TSA and TAATumor antigenExpressing cellsSpeicfic

13、ityAntigenicityOriginTSAtumor cellshighstrongPhysical and chemical agentsVirussilent genes or mutant cell genes Clonal antigenTAATumor cells normal cellslowweakMutant cell genesNormal cell genesOncofetal antigenDifferential antigen（二）根據(jù)腫瘤發(fā)生情況分類理化因素誘發(fā)：特異性高而抗原性弱，個(gè)體特異性明顯，少見。 如紫外線、X線暴露病毒誘發(fā)：抗原性較強(qiáng)而特異性較差，較

14、為普遍。 如EBV-淋巴瘤、鼻咽癌；HBV-肝癌等自發(fā)性腫瘤抗原：多類腫瘤為自發(fā)性，其抗原可類似于理化誘發(fā)或病毒誘發(fā)； 與癌基因與抑癌基因的失活有關(guān)。如HER-2/neu與乳腺癌，Bcr/Ab1融合蛋白與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

15、therapy to augment specific immunity（三）腫瘤抗原的用途胚胎抗原是指在胚胎發(fā)育階段由胚胎組織產(chǎn)生的正常成分，在胚胎后期減少，出生后逐漸消失，或僅存留極微量。但當(dāng)細(xì)胞癌變時(shí)，此類抗原可重新合成而大量表達(dá)，又稱為分化抗原。如PSA、黑色素瘤gp100和MART-1等?？煞譃閮煞N：分泌性抗原：Alpha-fetoprotein (AFP)腫瘤細(xì)胞膜表達(dá)抗原：Carcinoembryonic antigen (CEA) Embryonic antigensHigh CEA level is normally restricted to cells of the gu

16、t, 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 signific

17、antly 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:

18、 clinical useAdjunct in diagnosisStaging and prognosisMonitoring response to therapyDetection of tumor recurrenceDegree of Expression is a Diagnostic ToolImmunohistochemistry - Cytology of ascites (fluid in abdomen)Stains positive for CEA - suggests the tumor is of colorectal origin(2) Alpha-fetopro

19、tein (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

20、 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-upMarkedly increased in most cases of hepatocellular carcinoma (HCC)

21、May be slightly elevated in benign liver diseaseNormalizes with response to treatment, increases with recurrenceSerum 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. AFP (ng/mL

22、)Time (years)HBsAg +HCC Resected4. 腫瘤的免疫逃逸機(jī)制腫瘤抗原能夠誘導(dǎo)機(jī)體免疫系統(tǒng)產(chǎn)生免疫應(yīng)答，但為何很多腫瘤仍能在機(jī)體內(nèi)進(jìn)行性生長，并導(dǎo)致宿主死亡？腫瘤的生長涉及到諸多方面，如腫瘤細(xì)胞特性、腫瘤細(xì)胞周圍微環(huán)境及宿主免疫系統(tǒng)等多方面。（1）腫瘤細(xì)胞的抗原缺失和抗原調(diào)變 Lack of tumor antigensAntigenic modulation: is a phenomenon that cell-surface tumor antigens are decrease or lose because of attack of hosts humoral

23、 immune.（2）腫瘤細(xì)胞MHC I類分子表達(dá)缺陷或低下或缺乏共刺激信號(hào)Induction of T Lymphocyte AnergyCD8+TCTumor CellAnergyMHC Class ICD8+TCTumor CellTc ActivationB7CD28(Co-stimulation)（3）腫瘤細(xì)胞的凋亡抵抗作用高表達(dá)多種抗凋亡分子（如Bcl-2），不表達(dá)或弱表達(dá)Fas等凋亡誘導(dǎo)分子，從而抵抗凋亡的誘導(dǎo)，逃避CTL的殺傷效應(yīng)。（4）腫瘤細(xì)胞的“逃逸”由于腫瘤細(xì)胞的迅速生長超越了機(jī)體抗腫瘤免疫效應(yīng)的限度，致使宿主不能有效地清除大量生長的腫瘤細(xì)胞。（5）腫瘤細(xì)胞導(dǎo)致的免疫抑制

24、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

25、 firewall? Startup the firewallImmune systemOur immune systemImmune organsImmune cellsImmune moleculesCancersImmunityvsDeath 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 immuni

26、tyAnti-tumor cytokines免疫系統(tǒng)抗腫瘤機(jī)制Innate immunityNatural killer (NK)Mononuclear macrophageTCR+ T cell 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, therefore detect “miss

27、ing 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 cellsTumor cellactivatedMon

28、onuclear macrophageMacrophage mediated tumor cytotoxicity;Antibody dependent cell mediated cytotoxicity;Complement dependent cytotoxicity;Anti-tumor cytokines (TNF, IL-12).TCR+ T cellThey are a minor group of T cells with sort of NK-like features. Its target cells are not hypersensitive to NK cells.

29、Killing tumor with MHC restriction or non-MHC restriction (usually)Secreting perforin and granzymeAnti-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 immunity is killing of tumor ce

30、lls 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 phagocytol

31、ysisDeblocking factor effectSpecific antibodies targeting tumor antigensAntibody-mediated immunityAnti-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

32、 factor (TNF)Direct or indirect cytotoxicity upon tumor cellscolony-stimulating factor (CSF)Immunomodulation三、策略篇1. 腫瘤的免疫預(yù)防提高機(jī)體免疫系統(tǒng)功能：飲食、運(yùn)動(dòng)、生活方式； 制備腫瘤相關(guān)病原體疫苗：HPV疫苗應(yīng)用于宮頸癌預(yù)防2. 腫瘤的治療SurgeryRadiotherapyChemotherapyImmunotherapy: aims to: enhance the immunity of host to kill tumor cells with high specifi

33、city and low side-effect. We usually combine above four methods to fight against tumors.3.腫瘤的免疫治療非特異性免疫治療特異性免疫治療主動(dòng)免疫治療過繼免疫治療1) 非特異性免疫治療免疫調(diào)節(jié)劑:非特異性增強(qiáng)宿主的免疫功能、激活宿主的抗腫瘤免疫應(yīng)答。BCG, OK432，CpG-DNA/ODN細(xì)胞因子：Interleukin, interferon, TNFBacillus Calmette-Guerin (BCG)可通過激活的T輔助細(xì)胞所產(chǎn)生的IL-2及IFN-等激活體內(nèi)的巨噬細(xì)胞及NK細(xì)胞或直接激活巨噬細(xì)胞，增強(qiáng)其殺傷活性。另外，BCG可做為免疫佐劑增強(qiáng)其他抗腫瘤藥物的治療效果。毒副作用較大。OK