《肿瘤微环境PPT参考幻灯片》由会员分享，可在线阅读，更多相关《肿瘤微环境PPT参考幻灯片（70页珍藏版）》请在金锄头文库上搜索。
1、肿瘤免疫中的正性和负性肿瘤免疫中的正性和负性免疫成份免疫成份居颂光居颂光1 细胞出版社以增刊方式向世界专门介绍中国细胞出版社以增刊方式向世界专门介绍中国免疫学研究免疫学研究国际著名的细胞出版社（Cell Press）近日推出新一期聚焦中国(Spotlight on China)，介绍近年来中国免疫学基础及临床研究的飞速发展，其电子版在细胞出版社及其子刊的网站上均能免费阅读或下载http:/ Knutson K, et al. Cancer Immunol Immunother 2005, 54: 721728APCTHTregCytoxic T cellsOthers IFNIL-2IL-12
2、GranzymePerforinAbsothersTumor microenvironment:3 肿瘤研究肿瘤研究肿瘤细胞研究肿瘤细胞研究一个世纪的观念：肿瘤是局部组织一个世纪的观念：肿瘤是局部组织/ /器官细胞异常生长形成的疾病器官细胞异常生长形成的疾病 肿瘤是个系统性疾病肿瘤是个系统性疾病 肿瘤是一种组织（间质、血管、微环境），不是一堆肿瘤细胞肿瘤是一种组织（间质、血管、微环境），不是一堆肿瘤细胞 免疫功能失控，肿瘤患者的免疫系统不是简单的低下：免疫功能失控，肿瘤患者的免疫系统不是简单的低下： 保护肿瘤生长的免疫细胞：功能增强保护肿瘤生长的免疫细胞：功能增强 抑制肿瘤细胞的免疫细胞：功能
3、低下抑制肿瘤细胞的免疫细胞：功能低下 4 肿瘤的免疫编辑肿瘤的免疫编辑免疫成分在肿瘤发生过程中免疫成分在肿瘤发生过程中的作用的作用5 Dunn G,et al.Nature immunology. 2002.3(11):991Elimination corresponds to immunosurveillianceThe host immune system and any tumor variant that has survived in the elimination process enter into the dynamic equilibrium: *lymphocytes an
4、d IFN- exert potent selection pressure. *A tumor bed is containing many genetically unstable and rapidly mutating tumor cells.Survival tumor variants that have acquired insensitivity to immunologic detection and/or elimination begin to expand in uncontrol manner.Dunn G,et al.Nature immunology. 2002.
5、3(11):9916 Solid tumors reach a certain size: Grow invasively, require an enhanced blood supply.Inflammatory signals leading to recruitment of cells of innate immune system: macrophages, DCs, -T, NK and NKT.Produce IFN-7 The initial IFN- starts a cascade of immune response:1.Induction of chemokines:
6、CXCL10,CXCL9,CXCL11.Block neovascularization of tumor, recruit macrophages, DCs ,-T, NK and other immune cells.2.Antiproliferation of developing tumor.3.The activation of cytocidal activity in macrophages and NK cells entering the tumor.Dead tumor cells or tumor cells debris are ingested by DC and a
7、re trafficked to the draining lymph node.8 1.Tumor growth is kept in check by the cytocidal NK and mocrophages. 2.CD4+T and CD8+T cells that are specific for tumor antigens are developing in draining lymph node.9 Tumor specific CD4+T and CD8+T cells home to tumor site along a chemokine gradient .10
8、Dunn G,et al.Nature immunology. 2002.3(11):991Elimination corresponds to immunosurveillianceThe host immune system and any tumor variant that has survived in the elimination process enter into the dynamic equilibrium: *lymphocytes and IFN- exert potent selection pressure. *A tumor bed is containing
9、many genetically unstable and rapidly mutating tumor cells.Survival tumor variants that have acquired insensitivity to immunologic detection and/or elimination begin to expand in uncontrol manner.11 肿瘤研究肿瘤研究肿瘤细胞研究肿瘤细胞研究一个世纪的观念：肿瘤是局部组织一个世纪的观念：肿瘤是局部组织/ /器官细胞异常生长形成的疾病器官细胞异常生长形成的疾病 肿瘤是个系统性疾病肿瘤是个系统性疾病 肿瘤
10、是一种组织（间质、血管、微环境），不是一堆肿瘤细胞肿瘤是一种组织（间质、血管、微环境），不是一堆肿瘤细胞 免疫功能失控，肿瘤患者的免疫系统不是简单的低下：免疫功能失控，肿瘤患者的免疫系统不是简单的低下： 保护肿瘤生长的免疫细胞：功能增强保护肿瘤生长的免疫细胞：功能增强 抑制肿瘤细胞的免疫细胞：功能低下抑制肿瘤细胞的免疫细胞：功能低下 12 肿瘤抗原肿瘤抗原Olivera J. Finn, Ph.D.N Engl J Med 2008;358:2704-15Olivera J. Finn, Ph.D.N Engl J Med 2008;358:2704-1513 肿瘤抗原的加工提呈肿瘤抗原的加工
11、提呈Olivera J. Finn, Ph.D.N Engl J Med 2008;358:2704-1514 肿瘤干细胞肿瘤干细胞15 Knutson K, et al. Cancer Immunol Immunother 2005, 54: 721728APCTHTregCytoxic T cellsOthers IFNIL-2IL-12GranzymePerforinAbsothersTumor microenvironment:16 N Engl J Med 2006;355:1253 - 1261.17 Cancer stem cellNature Reviews Cancerdoi
12、:10.1038/nrc1232Tumor Heterogeneity and Cancer Stem Cells18 免疫成分在肿瘤微环境中免疫成分在肿瘤微环境中的的失衡失衡19 Nature.2005,5:26320 21 22 23 24 25 肿瘤微环境中的免疫细胞肿瘤微环境中的免疫细胞26 TH17 cells in tumour immunity andImmunotherapy. NATuRE REVIEWS | Immunology. doi:10.1038/nri2742Differentiation of helper T cell subsets27 28 TH17 ce
13、lls and antitumour immunity29 30 肿瘤微环境中的抑制性成分Treg细胞31 Treg细胞定义1995由Sakaguchi等发现了机体重要的负性免疫调节成分调节性CD4+CD25+ T细胞（regulatory T cell, Treg）。随后的研究根据细胞内标记分子Foxp3和细胞膜分子CD127表达与否，将经典的Treg细胞定义为CD4+CD25+ Foxp3+CD127low/neg T细胞。通过细胞间接触依赖机制发挥作用或分泌IL-10和TGF-等细胞因子，Treg细胞抑制CD4+25-T细胞、CD8+T细胞和树突状细胞等其他免疫细胞的活性和功能。32 大
14、量的研究报道表明:CD4+CD25+Treg细胞是抑制机体抗肿瘤免疫应答的关键成分之一，例如：Woo等发现在非小细胞肺癌和卵巢癌患者的肿瘤浸润淋巴细胞中Treg的含量明显增多；在胃肠道肿瘤患者中CD4+CD25-T细胞明显减少而Treg细胞数量增多，而且Treg细胞数量的增高与较差的预后和较低的生存率高度相关；Curiel 等报道，在卵巢癌中Treg细胞能抑制T细胞介导的特异性抗肿瘤免疫应答，并且有利于肿瘤的生长；因此研究者希望通过减少Treg细胞的数量或降低其活性来开辟治疗肿瘤免疫治疗的新途径。例如，以Foxp3为靶点清除荷瘤小鼠体内的Treg细胞后肿瘤会消退。33 Treg细胞的作用机制3
15、4 非小细胞性肺癌（NSCLC）与Treg新亚群35 Fig 136 Fig.237 Fig 338 Fig 439 CD8+TCD8+T细胞在肿瘤免疫中的作用细胞在肿瘤免疫中的作用肿瘤微环境中的肿瘤微环境中的“正性正性”免疫成分免疫成分40 Gadd45-/- mice or Het/WT mice were injected into intradermally of flank skin with 2.5X104 B16 cells/mouse.Tumor sizes were measured every 2 days.Tumor inject siteGadd45b KO mice
16、were challenged with melanoma cells: B16 Freeze down the tissue of tumor site.41 Fig 4 Gadd45-/- mice or WT mice were injected subcutaneously with 2.5X104 B16 cells/mouse, tumor sizes were measured every 2 days. These data are from 3 separated experiments.42 5.Both WT and Gadd45b KO T cells are able
17、 to infiltrate into tumor sites.43 Gadd45-/- mice or WT mice were injected intradermally of flank skin with 5X104 B16 cells/site/20ul PBSSkin of injected sites or opposite sites was resected and freeze down immediatelySpleen Cells Adoptive Transfer and B16 inoculationTumor inject siteCheck tumor for
18、mation from injected sites500 RadWTKO500 RadDonorHost44 6. Gadd45 is important for lymphocytes in tumor surveillanceP0.05*45 CD4+T Cells Adoptive Transfer and B16 inoculation500 RadWT CD4+TKO CD4+T500 RadDonor HostWT splenocytes depleted CD4+TWT splenocytes deplete CD4+T+46 7. Gadd45b KO does not af
19、fect function of CD4+T cells in tumor surveillanceKO: Transfer with CD4+T cell depleted spleen cells from WT mice +CD4+T cells from Gadd45b KO micePBS: Only transfer PBSWT: Transfer with CD4+T cell depleted spleen cells from WT mice +CD4+T cells from Gadd45b Het or WT mice47 CD8+T Cells Adoptive Tra
20、nsfer and B16 inoculation500 RadWT CD8+TKO CD8+T500 RadDonor HostWT splenocytes depleted CD8+TWT splenocytes deplete CD8+T+48 8. Gadd45b KO causes function defect of CD8+T cells in tumor surveillanceKO: Transfer with CD8+T cell depleted spleen cells from WT mice +CD8+T cells from Gadd45b KO micePBS:
21、 Only transfer PBSWT: Transfer with CD8+T cell depleted spleen cells from WT mice +CD8+T cells from Gadd45b Het or WT miceP0.05*49 Gadd45b is expressed in CD8+T cells during their activationFigure 1 Gadd45b message is induced by TCR signaling and costimulation. Naive CD8+ T cells were stimulated wit
22、h platebound anti-CD3 (-CD3) plus -CD28 and Th1 condition for 0h,1 h, 12h, 24h, 48h and 96h. The Gadd45b message was detected with RT-PCR.50 2. Gadd45 is important for the function of CD8+T cells. IL12/IL18-CD351 52 MAP kinase profile activated in CD8+T cells-CD3 (10 g/ml)IL-12(10 ng/ml) + IL-18 (30
23、 ng/ml)Figure 3 Gadd45 mediates p38 activation by TCR signaling or IL-12 plus IL-18 in CD8+T cells. (a) Effector CD8+T cells were stimulated (times, above lanes) with plate-bound anti-CD3 (-CD3; 10 g/ml) or (b) IL-12(10 ng/ml) and IL-18 (30 ng/ml). Cell extracts were analyzed by immunoblot with anti
24、-phospho-ERK (-phospho-ERK), -phospho-JNK and -phospho-p38. p-, phosphorylated. 53 Gadd45b KO causes function defect of tumor infiltrating CD8+T cellsFig 5 Gadd45 KO cause tumor infiltrating CD8+T cell function defect in vivo. Tumor mass was removed at day 13 after B16 F0 cells inoculation and diges
25、ted with collagenase I. Cells were stimulated with phorbol 12-myristate 13-acetate (50 ng/ml) and ionomycin (500 ng/ml) for 6 h and incubated for the last 3 h with Brefeldin A. Cells producing IFN- was identified with intracellular cytokine staining.54 Type, Density, and Location of Immune Cells Wit
26、hin Human Colorectal Tumors Predict Clinical OutcomeGalon J, et al. 29 SEPTEMBER 2006 VOL 313 SCIENCE55 Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical OutcomeGalon J, et al. 29 SEPTEMBER 2006 VOL 313 SCIENCE(B) Comparison of the mean of immune cell densit
27、ies in the CT and IM from patients with tumor recurrence (black bars) or without tumor recurrence (white bars).56 肿瘤微环境中的Immune checkpointsNATURE REVIEWS | CANCER 2012 doi:10.1038/nrc3239 57 Multiple co-stimulatory and inhibitory interactions regulate T cell responses 58 Immune checkpoints regulate
28、different components in the evolution of an immune response59 Two general mechanisms of expression of immune-checkpoint ligands on tumour cells 60 Implications of the adaptive immune resistance mechanism for combinatorial immunotherapy of cancer. 61 62 Clinical responses and immune-mediated toxiciti
29、es on antibody blockade of the CTLA4 mediated immune checkpoint.63 Blockade of PD-1 or CTLA-4 Signaling in Tumor Immunotherapy.10.1056/nejme120594364 肿瘤微环境中的免疫成分正与负的肿瘤微环境中的免疫成分正与负的相对性相对性65 SGN-40 CP870,893 CHIR-12.12B lymphomaSolid tumorMultiple myelomaThree CD40mAbs in preclinical trials66 CD40 sig
30、naling regulates angiogenesis. Giving blood: a new role for CD40 in tumorigenesis Bergmann S, Pandolfi PP. J Exp Med. 2006 Oct 30;203(11):2409-12. Epub 2006 Oct 16 67 Growth factorsTumorvasculatureDisseminatingtumor cellsInvasionCell cycle controlProliferatingtumor cellsAngiogenesisSignal transductionDouble-edged weapon single-edged for tumor?68 Knutson K, et al. Cancer Immunol Immunother 2005, 54: 721728APCTHTregCytoxic T cellsOthers IFNIL-2IL-12GranzymePerforinAbsothersTumor microenvironment:69 关于实验70
