医学免疫学：16 肿瘤免疫

1、Immunity to tumorsContent 1. General Features 2. Tumor antigen3. Immune Responses4. Evasion of Immune Responses5. Immunotherapy Cancer is a major health problem worldwide and one of the most important causes of morbidity and mortality in children and adults.Robin BushThe sister of George W. Bush, di

2、e from leukemia,at the age of 4.Walt DisneyThis famous animator, producer and co-founder ofthe corporation known as The Walt Disney Company died at the age of 65 from lung cancer,making him one of the most famous celebritiesto have died from smoking.Paul NewmanPaul Newman was of course a great actor

3、,but was known well for his healthy line of food.He struggled with lung cancer, and passed awayon September 26, 2008,at the age of 83.General Features Tumor express antigens that are recognized as foreign by the immune system of the tumor-bearing host.Immune responses frequently fail to prevent the

4、growth of tumors.The immune system can be activated by external stimuli to effectively kill tumor cells and eradicate tumors.Tumor Antigen Immune responses frequently fail to prevent the growth of tumorsFirst, tumor cells are derived from host cells. Second, the rapid growth and spread of tumors Thi

5、rd, specialized mechanisms for evading host immune responses. The immune system can be activated by external stimuli to effectively kill tumor cells and eradicate tumors. - Active immunotherapy; - Passive immunotherapy.Steven A. Rosenberg Steven A. Rosenberg is a leading cancer researcher and surgeo

6、n. He is credited with developing the use of IL-2 and immune cells for the treatment of patients with melanoma in a procedure termed adoptive cell transfer.LAKTILIL-2TCR gene transfer Combination with chemotherapyActivated immune cell adoptive Transfer for tumor therapyContent 1. General Features 2.

7、 Tumor antigen3. Immune Responses4. Evasion of Immune Responses5. ImmunotherapyTumor Antigen The earliest classification:Tumor-specific antigenTumor-associated antigenTumor Antigen Tumor-specific antigen Antigen that are expressed on tumor cells but not on normal cells were called tumor- specific an

8、tigens; some of these antigens are unique to individual tumors, whereas others are shared among tumors of the same type. Tumor Antigen Tumor-associated antigen Tumor antigens that are also expressed on normal cells were called tumor-associated antigens; in most cases, these antigens are normal cellu

9、lar constituents whose expression is aberrant or dysregulated in tumorsTumor Antigen Tumor Antigen The modern classification relies on the molecular structure and source of the antigenTumor Antigen Tumor Antigen Type of antigenExamples of human tumor antigensProducts of oncogenes, tumor suppressor g

10、enesOncogenes: Ras mutations (10% of human carcinomas), p210 product of Bcr/Abl rearrangements (CML), overexpressed Her-2/neu (breast and other carcinomas)Tumor supressor genes: mutated p53 (present in 50% of human tumors)Mutants of cellular genes not involved in tumorigenesisp91A mutation in mutage

11、nized murine mastocytoma; various mutated proteins in melanomas recognized by CTLsProducts of genes that are silent in most normal tissuesCancer/testis antigens expressed in melanomas and many carcinomas; normally expressed mainly in the testis and placentaProducts of overexpressed genesTyrosinase,

12、gp100, MART in melanomas (normally expressed in melanocytes)Products of oncogenic virusesPapillomavirus E6 and E7 proteins (cervical carcinomas)EBNA-1 protein of EBV (EBV-associated lymphomas, nasopharyngeal carcinoma)SV40 T antigen (SV40-induced rodent tumors)Oncofetal antigensCarcinoembryonic anti

13、gen (CEA) on many tumors, also expressed in liver and other tissues during inflammationAlpha-fetoprotein (AFP)Glycolipids and glycoproteinsGM2 GD2 on melanomasDifferentiation antigens normally present in tissue of originProstate-specific antigenMarkers of lymphocytes: CD10, CD20, Ig idiotypes on B c

14、ellsContent 1. General Features 2. Tumor antigen3. Immune Responses4. Evasion of Immune Responses5. ImmunotherapyImmune Responses to TumorsT lymphocytesAntibodiesNK cellsMacrophagesImmune Responses to TumorsT lymphocytes The killing of tumor cells by CD8+ CTLImmune Responses to TumorsT lymphocytesIm

15、mune Responses to TumorsT lymphocytesT lymphocytes：CD4+ T cellsTNF/ IFN-Immune Responses to TumorsAntibodiesAntibodies: the role of Ab in tumor elimination in vivo is rarely seen.The killing of tumor cells by activating complement or by ADCCImmune Responses to TumorsComplement SystemImmune Responses

16、 to TumorsImmune Responses to TumorsNK cells NK cells kill many types of tumor cells, especially cells that have reduced class I MHC expression and can escape killing CTLs.NK cells preferentially kill MHC I-deficient cells.Engagement of inhibitory NK cell receptors such as KIR and CD94/NKG2 by class

17、 I MHC molecules delivers an inhibitory signal that counteracts the activation signal.Immune Responses to TumorsNK cellsImmune Responses to TumorsMacrophages Dual role of macrophages in tumor growth and angiogenesis:They activate and present tumor antigens to T cells, which are then activated to kil

18、l tumor cells.However, tumor cells are often capable of escaping the immune machinery. As the immune surveillance is not sufficient anymore, tumor-associated macrophages contribute to tumor progression.Immune Responses to TumorsImmune Responses to TumorsTumor-associated macrophages In contrast, M2 m

19、acrophages ( tumor-associated macrophages) contribute to tumor progression by secreting VEGF, TGF-beta and other soluble factor to promote tumor angiogenesis.Summary on Antitumor Effector MechanismsCTLNK cellMacrophageHumoralMechanismsTumor cellContent 1. General Features 2. Tumor antigen3. Immune R

20、esponses4. Evasion of Immune Responses5. ImmunotherapyThe key of tumor growth, migration and metastasis is that tumor cells evade immune destruction, often called tumor escape.Turk MJ, J.Exp.Med. 2004, 200(6):771-782Hori S: Science,2003, 299:1057-1061Jun Shimizu et al: Nat. Immunology. 2002,3(2): 13

21、5-142Shevach. EM: Nat Rev. Immunol. 2002, 2:389-400Evasion of Immune ResponsesIntrinsic mechanisms of immune evasion by tumor cells.Extrinsic cellular suppression of antitumor immunity.Evasion of Immune ResponsesLack of Neo-antigensIntrinsic mechanisms of immune evasionTumor lose expression of antig

22、en that elicit immune responsesLack of class I MHCClass I MHC expression may be down-regulated on tumor cells so that they cannot be recognized by CTLs.Intrinsic mechanisms of immune evasionLack of co-stimulatorymoleculesIntrinsic mechanisms of immune evasionThe products of tumor cells may suppress

23、antitumor immune responses.(TGF-beta, IL-10)Intrinsic mechanisms of immune evasionEvasion of Immune ResponsesClass I MHC expression may be down-regulated on tumor cells so that they cannot be recognized by CTLs.Tumor lose expression of antigen that elicit immune responses.Tumors may fail to induce C

24、TLs because most tumor cells do not express costimulators or class II MHC molecules.The products of tumor cells may suppress antitumor immune responses.Tumor antigens may induce specific immunologicRegulatory T cells (CD4+CD25+Treg);Tumor-associated macrophages: - have a M2 phenotype and secrete cyt

25、okines such as IL-10, TGF- and prostaglandin E2 to suppress T cell responses. Myeloid-derived suppressor cells (MDSCs): Precursors of DCs, monocytes, and neutrophils . Extrinsic cellular suppression of antitumor immunityCD4+CD25+ Treg：Negative regulatorExisting a large number of CD4+CD25+ Tregs in T

26、ILsRegression of the tumorigenesis if deleting the CD4+CD25+ TregTyler J. Curiel et al: Nature Medicine. 2004, 10(9):942-949 Zhang, L et al: N. Engl. J. Med. 2003, 348:201-213Evasion of Immune ResponsesContent 1. General Features 2. Tumor antigen3. Immune Responses4. Evasion of Immune Responses5. Im

27、munotherapyImmunotherapyHistory Cancer Immunosurveillance Hypothesis (Controversy to Resolution) Inheritable genetic changes must be common in somatic cells and a proportion of these change will represent a step toward malignancy. It is an evolutionary necessity that there should be some mechanism f

28、or eliminating or inactivating such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character - Sir MacFarlane Burnet, 1964 Fundamental Prediction: Immunodeficient individuals should show a significant increase in tumor incidence. However, Athymic-nude

29、 mice and normal mice showed no differences in either latent period or incidence of local sarcomas or lung adenomas within 120 days after administration of 3-methylcholanthrene at birth - Stutman O, et al. Science 183(4124): 534. 197427 years later. Resolution Increased Incidence of MAC-Induced Tumo

30、r Detected In Mice With Well-Defined Genetic Immunodeficiencies. Shankaran et al. Nature 410: 1107-1111 2001 An accumulation of immune cells at tumor sites correlates with improved prognosis. Zhang et al. N Engl J Med 348: 203-213 2003 First human melanoma tumor antigen (MAGE-1) was identified. T Bo

31、on et al. Science, Vol 254, Issue 5038, 1643-1647 1991 ImmunotherapyImmunotherapy Active immunotherapy Passive immunotherapyImmunotherapyActive immunotherapyVaccinationAugmentation of host immunity to tumors with cytokines and costimulatorsImmunotherapyActive immunotherapy-VaccinationKilled tumor va

32、ccinePurified tumor antigensProfessional APC-based vaccinesCytokine- and costimulator-enhanced vaccinesDNA vaccinesViral vectorsImmunotherapyTumor BiopsyVaccine ProductionLeukapheresisDendritic CellsCo-culture+FusionMyeloma cellTumor Idiotype ProteinAs tumor specific- antigen+Immunization withAntige

33、n-pulsed DCsDendritic Cell- Based VaccinesRegression of Lymphoma following vaccination with Id-pulsed DCLevy R, Englman E, et al. Blood 2002, 90: 1517-1526Immunotherapy2011年度诺贝尔生理或医学奖2011 Nobel Prize Jules A. HoffmannBruce A. BeutlerRalph M. SteinmanProstate Cancer Therapeutic Vaccine Provengehas been approved by FDA in 2010 First FDA-approved cance