肿瘤与免疫-肿瘤免疫治疗-PPT精品课件.pptx

1、概概 述述主动免疫疗法主动免疫疗法 被动免疫疗法被动免疫疗法Paul Ehrlichs magic bullet concept:100 years of progress, Nature Reviews/Cancer Vol.8, 2008概概 述述NATURE REVIEW/CANCER, 2008,Vol.8:299-307 肿瘤免疫治疗分为肿瘤免疫治疗分为主动免疫疗法主动免疫疗法和和被动免疫疗法被动免疫疗法两大两大类。前者着重激发机体抗肿瘤免疫应答能力；后者向宿主类。前者着重激发机体抗肿瘤免疫应答能力；后者向宿主转移有抗肿瘤活性的治疗因子或细胞，抑制肿瘤生长。转移有抗肿瘤活性的治疗因子

2、或细胞，抑制肿瘤生长。 肿瘤免疫疗法肿瘤免疫疗法的分类及常用的生物制剂的分类及常用的生物制剂 分类分类治疗治疗因子或细胞因子或细胞 主动免疫疗法主动免疫疗法非特非特异性异性 BCG、CpG ODN、HSP、IFN- 等等 特异性特异性 减减毒或灭活的瘤苗毒或灭活的瘤苗、修饰、修饰的瘤苗的瘤苗、肿瘤抗原肿瘤抗原肽肽疫苗和基因重组产物疫苗和基因重组产物 被动免疫被动免疫疗法疗法非特异性非特异性细胞因子诱导的杀伤细胞细胞因子诱导的杀伤细胞（CIK）淋巴因子激活的杀伤细胞淋巴因子激活的杀伤细胞（LAK）DCDC介导的免疫治疗介导的免疫治疗 特异性特异性肿瘤浸润淋巴细胞肿瘤浸润淋巴细胞（TIL)抗体抗体

3、（Antibody）免疫偶免疫偶联联物物（Immuno-conjugates）嵌合抗原受体（嵌合抗原受体（CAT） BCG: Bacille Calmette-Guerin, CpG ODN: CpG Oligodeoxynucleotide, HSP: heat shock protein, CIK: cytokine inducing killer cell, LAK: lymphokine activated killer cell, TIL: tumor-infiltration lymphocytes, CAT：chimeric antigen receptorApproved im

4、mune therapies for cancerAntibody therapy of cancer. NATURE REVIEWS.CANCER VOLUME 12 APRIL 2012 ADCC, antibody-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; CLL, chronic lymphocytic leukaemia; CTLA4, cytotoxic T lymphocyte-associated antigen 4; EGFR, epidermal growth facto

5、r receptor; FDA, US Food and Drug Administration; IgG, immunoglobulin G; INFa; interferon-a; NHL, non-Hodgkins lymphoma; NSCLC, non-small-cell lung cancer; SCCHN, squamous cell carcinoma of the head and neck; VEGF, vascular endothelial growth factor. *Based on information from the European Medicines

6、 Agency. Not recommended for patients with colorectal cancer whose tumours express mutated KRAS. 一、非特异性主动免疫疗法一、非特异性主动免疫疗法二、特异性主动免疫疗法二、特异性主动免疫疗法主动免疫治疗主动免疫治疗 (Active Immunotherapy) 非特异性地激发机体的免疫系统，增强抗肿瘤免疫应非特异性地激发机体的免疫系统，增强抗肿瘤免疫应答能力，而达到杀伤肿瘤答能力，而达到杀伤肿瘤细胞。细胞。1 1. .免疫因子免疫因子 胸腺素(Thymosin)，转移因子(Transter fact

7、or) 免疫核糖核酸(Immune RNA)细胞因子: IFN-, IFN-, IFN-, IL-2, TNF-等2.2.微生物制剂微生物制剂 卡介苗(BCG)，CpG寡聚脱氧核苷酸(CpG ODN)3.3.化学合成药物化学合成药物 左旋咪唑(Levamisole，LMS) 4.4.中药制剂中药制剂(滋阴、补气、补血) 人参、黄芪等(主要为多糖成分) 一、非特异性主动免疫疗法一、非特异性主动免疫疗法卡介苗卡介苗制剂制剂 牛型结核杆菌或其细胞壁成分或细胞骨架成分，牛型结核杆菌或其细胞壁成分或细胞骨架成分，BCG中的有效成分是中的有效成分是胞壁酰二肽胞壁酰二肽(muramyl dipeptide，

8、MDP)。作用作用机制机制 直接直接活化活化M，刺激，刺激M 表达表达IL-6、IL-1, 增强增强IFN- 对对 M的刺激作用。的刺激作用。 刺激刺激特异性特异性TDTH的产生，间接活化的产生，间接活化M。 刺激刺激NK细胞增殖。细胞增殖。 非特非特异性刺激单核巨噬细胞。异性刺激单核巨噬细胞。 促进促进IL-2和和IL-4对对B细胞的作用。细胞的作用。临床临床应用应用 黑色素瘤黑色素瘤：瘤灶内直接注射：瘤灶内直接注射 浅浅表性膀胱癌：膀胱内滴注表性膀胱癌：膀胱内滴注卡介苗的临床应用卡介苗的临床应用（黑色素瘤）（黑色素瘤） 皮肤转移灶内皮肤转移灶内BCGBCG直接注射可使直接注射可使60%60

9、%左右接受注射的病灶消退，而且有左右接受注射的病灶消退，而且有15%15%未接受注射的病灶也消退，提示局部注射可导致全身性抗肿瘤免疫的未接受注射的病灶也消退，提示局部注射可导致全身性抗肿瘤免疫的建立。总共包括建立。总共包括269269名患者的名患者的1616项使用这一方法的研究都获得不同程度的项使用这一方法的研究都获得不同程度的疗效，完全缓解率最高达疗效，完全缓解率最高达90%(90%(范围范围7-90%)7-90%)，部分缓解率范围为，部分缓解率范围为5-50%5-50%。 在一项结合放疗的试验中，在一项结合放疗的试验中，74%74%患者获得完全缓解，另外患者获得完全缓解，另外5%5%患者获

10、得患者获得部分缓解。部分缓解。 BCGBCG瘤内注射疗法可提高患者生存率。不用瘤内注射疗法可提高患者生存率。不用BCGBCG治疗的皮肤癌复发患者，治疗的皮肤癌复发患者，存活时间的中值为存活时间的中值为13.313.3月，而接受月，而接受BCGBCG瘤内注射患者的瘤内注射患者的5 5年生存率达年生存率达27%27%。有相当一部分原发性黑色素瘤患者经皮内注射有相当一部分原发性黑色素瘤患者经皮内注射BCGBCG治疗后，长期存活。治疗后，长期存活。卡介苗的临床应用卡介苗的临床应用（浅表性膀胱癌）（浅表性膀胱癌） BCG BCG膀胱内滴注可以消除肉眼可见的浅表性膀胱癌，并能预防复发。膀胱内滴注可以消除肉

11、眼可见的浅表性膀胱癌，并能预防复发。 膀胱内注射膀胱内注射BCGBCG用于预防膀胱癌复发，可以显著延迟疾病的进展，延用于预防膀胱癌复发，可以显著延迟疾病的进展，延长保留膀胱的时间，提高总存活率。长保留膀胱的时间，提高总存活率。5 5项追踪期范围为项追踪期范围为12-6012-60月的随机研究月的随机研究发现，具有高度复发危险的患者，用膀胱内注射发现，具有高度复发危险的患者，用膀胱内注射BCGBCG治疗者，治疗者，70%70%保持无瘤；保持无瘤；而用反复尿道内切除者，仅有而用反复尿道内切除者，仅有31%31%的患者保持无瘤。的患者保持无瘤。报道实例报道实例CpGCpG寡聚脱氧核苷酸寡聚脱氧核苷酸

12、Activation of innate and adaptive immunity by TLR9 activation. Among human immune cells, only B cells and pDCs constitutively express TLR9. These cells endocytose DNA into an endosomal compartment where it binds to TLR9, forming a signaling complex. If the DNA contains unmethylated CpG motifs, TLR9

13、is stimulated, and the cell becomes activated. In pDCs, this results in type I IFN secretion, which activates NK cells, monocytes, and other APCs, and in the pDC maturation into a more effective APC able to activate naive T cells. Opposing these immune boosting effects, pDCs activated through TLR9 a

14、lso mediate immune-suppressive effects through counter regulatory factors such as indoleamine 2,3-dioxygenase (35, 36) and the generation of Tregs. In B cells, TLR9 stimulation results in the secretion of proinflammatory cytokines, such as IL-6, and in the release of immune regulatory cytokines that

15、 might limit the intensity of the inflammatory response, such as IL-10. TLR9 activation of B cells confers a greatly increased sensitivity to antigen stimulation and enhances their differentiation into antibody-secreting plasma cells. On balance, these immune effects of CpG DNA generally promote str

16、ong Th1 CD4+ and CD8+ T cell responses. However, the concurrent activation of counter regulatory pathways such as the induction of Tregs limit TLR9-induced immune activation, offering a potential for enhancing the therapeutic efficacy of TLR9 agonists by coadministration of antagonists of one or mor

17、e of these inhibitory pathways.细胞因子细胞因子Function of cytokines in host defense 上调免疫细胞的表面分子和受体的上调免疫细胞的表面分子和受体的表达；表达； 促进促进DCDC细胞的成熟细胞的成熟, ,增强增强T T细胞的细胞的增殖、分化和增殖、分化和CTLCTL的活的活 化和效应功能，化和效应功能，刺激刺激B B细胞产生抗体，提高细胞产生抗体，提高NKNK细胞活性，细胞活性， 激发巨噬细胞等产生抗肿瘤免疫应答；激发巨噬细胞等产生抗肿瘤免疫应答； 促进免疫效应细胞释放淋巴毒素和效应分子杀伤肿瘤；促进免疫效应细胞释放淋巴毒素和效

18、应分子杀伤肿瘤； 促进肿瘤细胞表达促进肿瘤细胞表达MHCMHC分子，增强肿瘤细胞的免疫原性分子，增强肿瘤细胞的免疫原性 和对效应细胞的敏感性；和对效应细胞的敏感性； 某些细胞因子具有直接破坏肿瘤细胞和促使其发生凋某些细胞因子具有直接破坏肿瘤细胞和促使其发生凋 亡的作用，如亡的作用，如TNFTNF。细胞因子杀伤肿瘤细胞的效应机制细胞因子杀伤肿瘤细胞的效应机制二、特异性主动免疫疗法二、特异性主动免疫疗法1. 肿瘤疫苗肿瘤疫苗2. 抗独特型抗体作为疫苗抗独特型抗体作为疫苗 肿瘤疫苗肿瘤疫苗 使用使用肿瘤疫苗的原理肿瘤疫苗的原理 肿瘤肿瘤疫苗分类疫苗分类 肿瘤肿瘤疫苗治疗肿瘤疫苗治疗肿瘤的可能影响因素

19、的可能影响因素使用肿瘤疫苗的原理使用肿瘤疫苗的原理 肿瘤细胞表达肿瘤抗原并被机体免疫系统肿瘤细胞表达肿瘤抗原并被机体免疫系统所识别；所识别； 肿瘤疫苗刺激主动特异性抗肿瘤应答免疫，肿瘤疫苗刺激主动特异性抗肿瘤应答免疫，激发或加强宿主免疫以消灭肿瘤；激发或加强宿主免疫以消灭肿瘤； 肿瘤患者中许多已知的和未知的因素（肿肿瘤患者中许多已知的和未知的因素（肿瘤免疫原性）造成了免疫应答的失败。瘤免疫原性）造成了免疫应答的失败。肿瘤疫苗分类肿瘤疫苗分类根据根据应用目的分类应用目的分类 预防性预防性肿瘤疫苗肿瘤疫苗治疗治疗性肿瘤疫苗性肿瘤疫苗 根据根据肿瘤疫苗中肿瘤抗原的存在形式分类肿瘤疫苗中肿瘤抗原的存在

20、形式分类细胞细胞疫苗疫苗 灭活肿瘤细胞、灭活肿瘤细胞、DC 、 DC/ /肿瘤融合细胞肿瘤融合细胞肿瘤抗原疫苗肿瘤抗原疫苗 肿瘤肿瘤细胞裂解物、肿瘤抗原、抗原肽细胞裂解物、肿瘤抗原、抗原肽基因工程基因工程疫苗疫苗 肿瘤抗原肿瘤抗原、细胞因子或协同刺激分子细胞因子或协同刺激分子等等 ( (基因重组产物基因重组产物) ) 基因基因转染转染DC、肿瘤细胞等肿瘤细胞等DNADNA疫苗疫苗 肿瘤抗原基因质粒肿瘤抗原基因质粒u肿瘤细胞肿瘤细胞疫苗疫苗uDC疫苗疫苗uDC /肿瘤融合细胞肿瘤融合细胞 细胞疫苗细胞疫苗 肿瘤细胞疫苗肿瘤细胞疫苗DC疫苗疫苗特征特征制备和应用制备和应用 DC /肿瘤融合细胞肿瘤

21、融合细胞 适用于大多数肿瘤抗原还未鉴定的肿瘤适用于大多数肿瘤抗原还未鉴定的肿瘤。肿瘤抗原的来源和应用肿瘤抗原的来源和应用 来源来源 举举 例例癌基因产物癌基因产物 ras12密码子突变密码子突变: 胰腺癌胰腺癌 BCR/abl重排产物重排产物: CML 静止基因产物静止基因产物 MAGE家族家族: 黑色素瘤，乳腺癌黑色素瘤，乳腺癌病毒基因产物病毒基因产物 EBV: Burkett淋巴瘤，鼻咽癌淋巴瘤，鼻咽癌 HPV: 宫颈癌宫颈癌 HBV: 肝细胞癌肝细胞癌组织特异性蛋白组织特异性蛋白(分化抗原分化抗原) 酪氨酸酶酪氨酸酶: 黑色素瘤黑色素瘤突变的抑癌基因产物突变的抑癌基因产物 P53: 多种

22、肿瘤多种肿瘤抗独特型抗体抗独特型抗体(Anti-Id-Ab) TCR Id: T细胞淋巴瘤细胞淋巴瘤肿瘤抗原疫苗肿瘤抗原疫苗mRNAMAGE-1蛋白309氨基酸HLA-Cw16HLA-A1161 169 EADPTGHSY SAYGEPRKL 开放阅读框 230 238MAGE-1基因X染色体q28区 外显子3 外显子2 外显子1MAGE-1.Cw16肽段 MAGE1MAGE1基因定位于基因定位于X X染色体染色体q28q28区，区，mRNAmRNA转录表达的转录表达的MAGE-1MAGE-1蛋白为蛋白为309309氨基酸，由氨基酸，由HLA-A1HLA-A1和和HLA-Cw16HLA-Cw1

23、6提呈的抗原肽位于提呈的抗原肽位于161161169169和和230230238238区域氨基酸序列。区域氨基酸序列。MAGE-1MAGE-1基因、编码蛋白和抗原肽基因、编码蛋白和抗原肽黑色素瘤特异性黑色素瘤特异性CTLCTL识别的黑色素细胞分化抗原肽识别的黑色素细胞分化抗原肽分化抗原分化抗原抗原肽结构抗原肽结构肽位置肽位置递呈分子递呈分子酪氨酸酶酪氨酸酶MLLAVLYCL1-9HLA-A2 YMNGTMSQV369-377HLA-A2 AFLPWHRLF(L)HLA-A24 SEIWRDIDF192-200HLA-B44Pmel 17/gp100KTWGQYWQV154-162HLA-A2

24、ITDQVQGSV209-217HLA-A2 YLEPGPVTA280-288HLA-A2 LLGDTATLRL457-466HLA-A2 VLYRYGSFSV476-485HLA-A2Melan-AMART-1(E)AAGIGILTV26(7)-35HLA-A2 ILTVILGVL32-40HLA-A2gp75TRP1HLA-A31制备和应用制备和应用An effective vaccine against human papilloma virus (HPV) induces antibodies that protect against HPV infection. Serotype 1

25、6 of HPV (HPV-16) is highly associated with the development of cervical cancer. In a clinical trial, 755 healthy uninfected women were immunized with a vaccine generated from highly purified noninfectious virus-like particles (VLP) consisting of the capsid protein L1 of HPV-16 and formulated with an

26、 alum adjuvant (in this case aluminum hydroxyphosphate sulfate). In comparison with the very low titers of antibody in placebo-treated uninfected women (green line), or women previously infected with HPV that received placebo (blue line), the women treated with the virus-like particle vaccine (red l

27、ine) developed high titers of antibody against the L1 capsid protein. None of these immunized women subsequently became infected by HPV-16. An anti-HPV vaccine marketed as Gardasil is now available and recommended for use in girls and young women as a protection from cervical cancer caused by HPV se

28、rotypes 6, 11, 16, and 18.PLG based 3D polymer scaffold vaccine to recruit and program immune cells to generate antitumor immunity. (a) Overall schematic of the vaccine. 1. SEM image of a PLG 3D scaffold; scale bar: 1000 mm. (b) Number of CD11c+ DCs isolated from the scaffold on day 14 post implanta

29、tion in response to 0, 400 ng, 3000 ng and 7000 ng of GM-CSF. (c) The number of CD11c+ CCR7+ DCs isolated from the scaffold loaded with PEI-ODN control, 10 mg PEI-CpG-ODN, 400 and 3000 ng GM-CSF and 400 and 3000 ng GM-CSF in combination with 10 mg PEI-CpG-ODN at day 7 after implantation. (d) A compa

30、rison of the survival of mice following prophylactic (left) and therapeutic (right) vaccination. In the prophylactic vaccination, mice were vaccinated with blank PLG scaffolds (Blank), antigen+ 100 mg CpG-ODN (Lys + 100CpG), antigen + 3000 ng GM-CSF + 10 mg CpG-ODN (Lys + 3000GM + 10CpG), antigen +

31、3000 ng GM-CSF + 100 mg CpG-ODN (Lys + 3000GM + 100CpG), or irradiated, GM-CSF-transduced B16-F10 cells (cell based). Mice were challenged (day 0 on graphs) with 105 B16-F10 melanoma tumor cells and monitored for the onset of tumor occurrence. In the therapeutic vaccination, mice were inoculated wit

32、h 5 X 105 B16-F10 cells and allowed to develop for 9 days and treated with blank PLG matrices (Blank), PLG matrices loaded with 3000 ng of GM-CSF and 100 mg of CpG-ODN (GM + CpG). Mice were also treated once (Vax, 1; at day 9), or twice (Vax, 2; at days 9 and 19) with PLG matrices incorporating GM-C

33、SF, CpG-ODN, and tumor lysates (Vax). Mice were also treated with 5 X105 irradiated, GM-CSF-transduced B16-F10 cells. Panels (c) and (d left) reproduced with permission 19, Copyright 2009, Nature Publishing Group. Panels (b) and (d right) reproduced with permission 20, Copyright 2009, The American A

34、ssociation for the Advancement of Science.Materials based tumor immunotherapy vaccines.Current Opinion in Immunology 2013, 25:238245 基因工程疫苗基因工程疫苗l修饰的肿瘤疫苗修饰的肿瘤疫苗 协同刺激分子、细胞因子基因修饰的协同刺激分子、细胞因子基因修饰的 肿瘤细胞肿瘤细胞 l重组病毒疫苗重组病毒疫苗 用已知肽的用已知肽的cDNA序列与灭活病毒重组序列与灭活病毒重组 产生的疫苗，可同时转入产生的疫苗，可同时转入MHC、B7等等 基因。基因。Enhancement o

35、f tumor cell immunogenicity by transfection of costimulator and cytokine genes. Tumor cells that do not adequately stimulate T cells on transplantation into an animal will not be rejected and will therefore grow into tumors. Vaccination with tumor cells transfected with genes encoding costimulators

36、or cytokines, such as IL-2, can lead to enhanced activation of T cells. This approach of using transfected tumor cells as vaccines has worked in mouse models, but clinical trials have not yet been successful.Tumor vaccines. Two types of tumor vaccines that have shown efficacy in clinical trials and

37、animal models are illustrated. Autologous dendritic cells are prepared from patients own peripheral blood cells. The dendritic cells are either pulsed with recombinant protein or transfected with a gene construct that expresses the protein. The construct may also express costimulatory molecules (not

38、 shown).Use of DNA vaccines raises both humoral and cellular immunity DNA疫苗疫苗 肿瘤肿瘤DNADNA疫苗由肿瘤抗原基因与质粒重组后形成，其中疫苗由肿瘤抗原基因与质粒重组后形成，其中肿瘤抗原基因随治疗的肿瘤的类型及选用的肿瘤抗原不同肿瘤抗原基因随治疗的肿瘤的类型及选用的肿瘤抗原不同而不同，质粒则是作为肿瘤抗原基因的载体。肿瘤而不同，质粒则是作为肿瘤抗原基因的载体。肿瘤DNADNA疫苗疫苗中常用的质粒有中常用的质粒有pSV2pSV2、pRSVpRSV、pcDNA3.1pcDNA3.1和和pC1pC1等，这些载体等，这些载体

39、一般都设计有真核基因表达调控序列（如增强子和启动子一般都设计有真核基因表达调控序列（如增强子和启动子等）、供目的基因插入的多克隆位点、转录终止序列以及等）、供目的基因插入的多克隆位点、转录终止序列以及可使质粒在大肠杆菌中保持并多拷贝复制的序列可使质粒在大肠杆菌中保持并多拷贝复制的序列ColEIColEI等等。 肿瘤肿瘤DNADNA疫苗的免疫接种有多种途径，包括直接注射、疫苗的免疫接种有多种途径，包括直接注射、基因枪免疫和电穿孔免疫等。不同免疫途径的免疫机制不基因枪免疫和电穿孔免疫等。不同免疫途径的免疫机制不同，所诱导的免疫保护力强弱和维持时间也不尽相同。肌同，所诱导的免疫保护力强弱和维持时间也

40、不尽相同。肌肉注射是最早采用的免疫途径，研究最充分，效果也较好。肉注射是最早采用的免疫途径，研究最充分，效果也较好。 肿瘤肿瘤DNADNA疫苗的临床应用目前报道较少，仅有少量进入疫苗的临床应用目前报道较少，仅有少量进入I/III/II期临床试验，如期临床试验，如gp100gp100和蛋白酪氨酸激酶用于治疗黑色和蛋白酪氨酸激酶用于治疗黑色素瘤、素瘤、CEACEA疫苗用于治疗结直肠癌、疫苗用于治疗结直肠癌、PSAPSA和和PSMAPSMA用于治疗前用于治疗前列腺癌、列腺癌、HPV-E6HPV-E6，E7E7用于治疗子宫颈癌以及用于治疗子宫颈癌以及NY-ESO-1NY-ESO-1用于用于治疗非小细胞

41、性肺癌等。治疗非小细胞性肺癌等。Appropriate utilization and regulation of DCs in vaccine design induce a much more potent CTL antitumor immune response. (a) Tumor antigen-loading techniques activate DCs ex vivo. (b) Targeted drugs facilitate the capture of tumor antigens by DCs and the expression of costimulatory m

42、olecules and MHC-II in vivo. (c) Stimulatory adjuvants induce maturation of DCs and enhance the activation of CTLs.肿瘤疫苗治疗肿瘤的可能影响因素肿瘤疫苗治疗肿瘤的可能影响因素肿瘤抗原选择肿瘤抗原选择MHC I、II类分子和共刺激分子的缺陷或降低类分子和共刺激分子的缺陷或降低诱导诱导T细胞细胞CTLA-4的表达的表达CD4+CD25+Foxp3+调节调节T T细胞的抑制作用细胞的抑制作用TH1/TH2细胞不平衡细胞不平衡免疫程序优化组合免疫程序优化组合(1)(1)抗原和佐剂的剂量及

43、途径应用恰当抗原和佐剂的剂量及途径应用恰当(2)(2)减轻肿瘤负荷减轻肿瘤负荷(3)(3)免疫活性细胞含量和功能检测免疫活性细胞含量和功能检测(4)(4)抑制性抑制性DCDC、TregTreg细胞、细胞、MSCMSC和抑制性巨噬细胞等含量分析和抑制性巨噬细胞等含量分析(5)(5)肿瘤治疗的干预手段联合应用肿瘤治疗的干预手段联合应用 Schematic illustration of human telomerase reverse transcriptase (hTERT) antigenic peptides presented by MHC class I complex on the t

44、umor cell surface. Multiple antigenic peptides derived from hTERT in tumor cell are recognized by immune cells. The peptides are generated by proteasome degradation of hTERT protein. The hTERT peptides are transported by the transporter associated with antigen processing into the ER where they are l

45、oaded onto MHC class I molecules and transported through the Golgi apparatus onto the cell surface. CD8+ cytotoxic T lymphocyte with specific receptors recognize and attack the tumor cell by the engagement of the T cell receptor with an MHC class I-hTERT peptide complex.Biochimica et Biophysica Acta

46、 xxx (2009) Telomerase in cancer immunotherapy (review) Model of human telomerase reverse transcriptase (hTERT) antigen stimulation of DCs, CD4+ T cells, and expansion of CD8+ T cells in vivo. (1) Telomerase hTERT antigen transfer and processing in APC, (2) antigen presentation from APC or tumor cel

47、ls to T cells, (3) interaction between CD4+ and CD8+ T cells, (4) Expansion of CD8+ CTLs that have sufficient telomeres, (5) CTLs with short telomeres undergo cell senescence and apoptosis, and (6) CD8+ cytotoxic lymphocytes attack the tumors expressing telomerase hTERT antigen.Hypothetical modes of

48、 action of dominant and cryptic immune epitopes in epitope-specific T cell clonal evasion or reactivation. (A) Dominant epitope to MHC class I forms a stable antigen-MHC class I complex that engages with its specific TCR at such high affinity that death of the T cell clone occurs. (B) An intermediat

49、e epitope with variable avidity to MHC class I forms antigen-MHC complexes that interact with its specific TCR discontinuously under particular conditions resulting in either elimination or activation of the T cell clone. (C) Cryptic epitope with low affinity to MHC class I forms an unstable antigen

50、-MHC class I complex that has a poor interaction with its specific TCR, resulting in the survival and continuous presence of the T cell clone specific to the cryptic epitope. (D) Position 1 tyrosine substitution (P1Y) or position 9 valine substitution (P9V) in the cryptic epitope enhances the crypti