医学免疫学课件：IL-21与肿瘤治疗

1、IL-21与肿瘤治疗目录Il-21&IL-21RIl-21介导的信号通路IL-21对免疫细胞的作用Il-21在肿瘤治疗的应用IL-212000年命名IL-2家族基因位于4q26-q27133个氨基酸四螺旋结构CD4+T细胞分泌（1）功能多样http:/www.ebi.ac.uk/pdbe/entry/pdb/2OQPIL-21R孤独受体受体复合体包括IL21R与c受体链IL-2家族公用激活方式（2）酪氨酸残基Janus kinase1（JAK1）和JAK3http:/pdb/ngl/ngl.do?pdbid=3TGX&preset=validationReport信号通路JAK/STAT通路（

2、3）Signal transducers and activators of transcription（STAT）STAT1，STAT3，STAT5停靠JAK激酶磷酸化脱离，组成二聚体入核，活化特异基因启动子Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015

3、, Article ID 696578, 15 pages信号通路phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)调节细胞周期（3）ras/raf/Mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinases (MAPK)细胞分裂（3）interferon-regulatory factor 4 (IRF4)+STAT3细胞凋亡（4）B细胞只有IL-21（5）激活toll like receptor（TLR）介导凋亡IL-21+BCR/CD

4、40促进增殖（5）激活Blimp1（6）促进分化Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pagesB细胞IL-21+IL-4（7）CD40+B细胞促进IgG1和IgG3分泌长效浆细胞的产生IL-21信号

5、的STAT3促进抗肿瘤抗体表达Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pagesB细胞IL21R缺失的小鼠（8）B细胞调节异常IgG1降低，IgE升高与自身免疫疾病的B细胞应答有关T细胞激活Bcl6和M

6、AF转录因子（9）促进滤泡辅助T细胞分化IRF-4DC抗原呈递后Tfh产生大量细胞因子，包括IL-21刺激B细胞二次免疫应答Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pagesT细胞促进CTL分化成熟 I

7、L-21+IL-15（10）可维持CTL的CD28表达与反应性增强IL-15介导的CTL增殖增强记忆CD8+T和原始CD8+T的扩增Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pagesT细胞L21R缺陷的

8、小鼠（10）CTL反应下降STAT1激活CD8+T细胞中的转录因子T-bet穿孔素和粒酶B的表达增强CTL运输CCR7有关C-C chemokine receptorMichela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 1

9、5 pagesT细胞IL-21+IL-2（11）刺激产生IL-10的type 1 regulatory T (Tr1)增殖和分化STAT3刺激Il-10的产生抑制APC和T细胞对抗原的反应Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article I

10、D 696578, 15 pagesNK细胞仅是调节功能（12）只有IL-21不会刺激NK细胞增殖IL-21+IL-2/IL-15（12）共刺激可促进NK细胞增殖已激活的NK高效的效应细胞更多的IFN-，穿孔素细胞毒素效应增强Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Vol

11、ume 2015, Article ID 696578, 15 pagesNK细胞STAT3（12）提高natural killer group 2, member D (NKG2D) 受体的表达STAT3缺失降低NKG2D的表达量IL-21+IL-7+IL-15+干细胞因子（SCF）激活KIRs，CD2和细胞裂解反应介导骨髓中CD34+的前细胞分化为成熟的NK细胞刺激NK凋亡限制NK反应的持续时间NK细胞IL-21不是NK细胞成熟分化的必要条件（12）IL21R缺失只是会降低针对NK敏感抗原的细胞毒作用，不会影响antibody-dependent cell-mediated cytotox

12、icity（ADCC）肿瘤中失去功能NK细胞IL-21刺激可以重新唤醒ADCC树突状细胞（DC）抑制作用（13）STAT3和Bim激活凋亡Granulocyte macrophage colony-stimulating factor（GM-CSF）可以部分抑制凋亡作用Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of I

13、mmunology Research Volume 2015, Article ID 696578, 15 pagesB-10/BregB-10分泌IL-10的B细胞亚群Il-20+CD40+T细胞（14） 刺激B细胞分化为Treg细胞分泌大量Il-10抑制免疫反应Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Imm

14、unology Research Volume 2015, Article ID 696578, 15 pagesB-10/BregB细胞白血病小鼠（14）注入诱导出的B-10细胞病情被抑制Il-21+TLR/BCR（14）可诱导出CD19+CD38+CD1d+IgM+CD147+ granzyme B+ Treg细胞与人类肿瘤周围的变异Breg细胞同型与肿瘤的免疫逃逸有关Treg抑制Treg的功能（15）刺激T细胞的生长中和Treg的抑制作用抑制 IL-2/TGF-信号（15）抑制Treg生长STAT3抑制分化的激活物Smad2/3负向调节Treg分化Michela Croce, Valen

15、tina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pagesTreg导致CD4+CD25 T 细胞对Treg细胞产生耐性与T细胞白血病相关（15）阻断IL-21/IL-21R轴有效抑制自身免疫疾病（15）Michela Croce, Valentina

16、 Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pages慢性B细胞淋巴白血病JAK/STAT （16）激活caspase-8 and caspase-3激活poly (ADP-ribose) polymerase (PARP) 激活p27Kip-1正向调节

17、Bcl-2 interacting mediator (BIM)B细胞凋亡慢性B淋巴细胞白血病CD40L和CpG oligodeoxynucleotide（16）正向调节IL-21R的表达IL-21+CpG oligodeoxynucleotide（16）凋亡分泌粒酶B抑制丝蛋白酶抑制剂B9治疗有效不只是本身凋亡，也会杀伤周围细胞慢性B淋巴细胞白血病效果会被其他信号干扰（16）IL-21+IL-4 导致CLL增殖对B-CLL的微环境建立有促进作用治疗效果有待改进滤泡状淋巴瘤（FL）JAK/STAT（17）促进Caspase-8 and -3 激活降低Bcl-2 表达增加proapoptotic

18、 Bax 表达细胞凋亡只对IL-21敏感细胞有效滤泡状淋巴瘤弥散性大B细胞淋巴癌（DLBCL）阻碍细胞周期激活caspase介导的细胞凋亡STAT激活C-Myc（18）刺激凋亡抑制抗凋亡蛋白Bcl-2 and Bcl-XL 蛋白表达套细胞淋巴癌（MCL）STAT1信号通路（18）增加BIK, NIP3, 和 HARAKIRI抑制抗凋亡蛋白BCL-2 and BCLXL/S抑制nuclear factor-kappaB (NF-B)信号促进细胞凋亡细胞疫苗表达IL-21的癌细胞（19）旁分泌效应刺激CTL，NK，B，效果强于IL-2 or IL-15IFN-，CXCL-9,10,11抗血管生成作

19、用抑制肿瘤形成，增强对同型肿瘤抗性细胞疫苗除了肿瘤细胞，其他细胞也能做成疫苗（19）DC-hgp100/mIL21对抗B16黑素瘤表达鼠IL-21的人脐带血干细胞（hUCBSC）抑制卵巢癌肿瘤治疗性分子IL-21可以加强治疗效应anti-CD25 mAb+分泌IL-21的乳腺癌细胞（20）增强抗原特异的T细胞反应以及IFN-的分泌有效率达到70%anti-CD4 mAb+分泌IL-21的神经胶质瘤细胞Treg（-）&CD8+细胞（+）免疫检查点与肿瘤细胞的免疫逃逸相关PD-1和PD-1LPD-1：激活的T细胞表面PD-1L：实体瘤细胞表面结合后抑制CTL的增殖转基因导入表达IL-21和可溶性P

20、D-1（21）治疗H22肝癌其他治疗方法鸡尾酒疗法其他治疗性单抗DNA疫苗IL-21治疗肿瘤的缺点作用的两面性NK细胞凋亡，抑制B细胞作用的复杂性不同的共刺激信号产生不同的效果效果不稳定副作用可溶性会在全身分布，产生不良反应，甚至自身免疫病总结IL-21可以激活与增强抗肿瘤免疫反应通过不同共刺激信号可以增强免疫疗法的效果需要提高效果的可控性参考文献（1）J. Parrish-Novak, S. R. Dillon, A. Nelson et al., “Interleukin 21 and its receptor are involved in NK cell expansion and r

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