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1、 Somatic mutations are not transmitted to progeny(后代), but germinal mutations may be transmitted to some or all progenyAngiogenesis in Breast Cancer肿瘤发生的机制肿瘤发生的机制pro-oncogeneSuppressor gene诱因Suppressor genepro-oncogene细细 胞胞 癌癌 变变 的的 分分 子子 机机 制制A正常细胞C带有致癌基因病毒感染的细胞B癌变细胞原癌基因基因启动抑制基因细胞按照指令 增殖然后停止原癌基因异常启
2、动抑制基因突变细胞增生失控细胞增生失控致癌基因进入胞核病毒在瘤变细 胞内大量繁殖第一节第一节 肿瘤和宿主免疫系统间的相互作用肿瘤和宿主免疫系统间的相互作用Immune cells killed a tumor cell The Tumors As a grafted tissueImmune Surveillance (recognizing abnormal cell)Escape from Escape from immunoimmuno-surveillance-surveillance逃脱免疫监视缺乏新抗原缺乏MHC I分子缺乏协同刺激分子可溶性抗原封闭抗体肿瘤分泌免疫抑制分子Tumo
3、r escape mechanismsICAM-1:intercellular adhesion molecule-1RCAS1: a growth inhibitory molecule, which react with T cell bearing their corresponding receptors and stop them in their tracks.1234567一、肿瘤诱发的细胞因子和免疫抑制一、肿瘤诱发的细胞因子和免疫抑制肿瘤分泌免疫抑制分子表 -1 免疫抑制性细胞因子对肿瘤浸润性淋巴细胞功能的作用 作用 TGF- IL-10 VEGFT细胞生长抑制 + - + C
4、TL分化抑制 + + + 细胞因子产生抑制 + + - T细胞无反应性诱导 + - - 细胞毒性作用下调 + + - 抗原呈递作用抑制 + + - Th1-Th2细胞平衡移至Th2细胞 + + - 粘附/协同刺激分子下调 + + - CTL介导裂解的抗性 - + -二、细胞毒细胞是免疫抑制性细胞因子的靶细胞二、细胞毒细胞是免疫抑制性细胞因子的靶细胞下调TGF- , IL-6, IL-10(-)凋亡 (1) 对凋亡的抵抗性 （2）表达FasL，并通过 Fas-FasL相互作用而杀灭浸 润的免疫效应细胞。a growth inhibitory molecule,三、肿瘤细胞中抗原处理机制的缺陷三、
5、肿瘤细胞中抗原处理机制的缺陷伴随蛋白多肽转运蛋白1、MHC I 类抗原呈递可溶性抗原封闭抗体缺乏协同刺激分子第二节第二节 肿瘤的免疫学治疗肿瘤的免疫学治疗IL-2 AbActive Non-specific BCG, Propionibacterium acnes(丙酸痤疮杆菌), levamisole(左旋咪唑), cytokine genes, etc.Specific killed tumor cells or their extract, recombinant antigens, idiotype, co-stimulatory molecule genes, etc.Passive
6、 Nonspecific LAK cells, cytokinesSpecific antibodies alone or coupled to drugs, pro-drug toxinsor radioisotope; bispecific antibodies; T-cellsCombined LAK cells and bispecific antibody* BCG: Bacillus Calmette Geurin is a bovine strain of Mycobacterium tuberculosis. Table 1. Immunotherapy of tumorsTy
7、pe of BRM examplesbacterial product BCG, P. acnes, muramyl di -peptide, trehalose dimycolatesynthetic molecules pyran, poly I:C, pyrimidinescytokines interferon IL-2, TNFTable 2. Non-specific active immunotherapy: biological response modifiers ( BRMs )activate macrophages and NK cells (via cytokines
8、)major effectinduce interferon productionactivate macrophages and NK cellsTUMOR CELL-S-S-Fab免疫毒素( 植物和细菌 ) 同位素( I131, I125, In111 ) 抗体导向化学疗法（甲氨喋呤,长春新碱,阿霉素） 裂解药物的酶一 抗体-S-S-as vehicles to targetMonoclonal anti-tumor antibodies have been used for indifferent forms for the treatment of cancer, because of
9、 their direct effect or as vehicles to target anti-cancer drugs, toxins and the nonspecific components of the hosts immune system to the site of tumor. In addition, such specific antibodies are also used in the diagnosis of metastatic lesions, otherwise not detectable by conventional radiologic mean
10、s.肿瘤相关抗原制备的单克隆抗体的应用Figure1. Recurrent melanoma( 黑色素瘤), unresponsive to radiotherapy, prior to immunotherapy with intralesional (病灶内的) injections of human monoclonal antibody to GM2 or GD2. GD3, a prominent ganglioside (神经节糖 苷)on the surface of melanoma cells.Figure 2. The same patient 2 years later
11、following complete regression of all disease.Recombinant Antibody Constructs. The development of an immune response frequently occurs in immunocompetent patients that have received murine monoclonal antibodies. These human antimurine antibodies, commonly referred to as HAMA, can alter the pharmacoki
12、netics of subsequent doses of radiolabeled antibodies through the formation of labeled immune complexes that are rapidly removed from the circulation before they can be delivered to the tumor. Recombinant DNA technology has been used to generate molecules that can help minimize this problem by decre
13、asing the fraction of the molecule that is of murine origin. Human/mouse chimeric antibodies, which consist of a murine variable region linked to a human constant region, and CDR-grafted, humanized antibodies, in which the murine component is limited to the hypervariable complementary determining regions, have been developed. A number of chimeric antibodies have been radiolabeled and their properties evaluated in clinical trials. By minimizing HAMA, these molecules should facilitate the use of multidose treatment radioimmunotherapy protocols; however, immune response to the antibody v
