2013——研究生讲座——肿瘤微环境简介 PPT.ppt

肿瘤微环境简介;;;Sid P. Kerkar and Nicholas P. Restifo. Cancer Res 2012;72:3125-3130.;肿瘤研究≠肿瘤细胞研究;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, γδ-T, NK and NKT. Produce IFN-γ;The initial IFN-γ starts a cascade of immune response: 1.Induction of chemokines:CXCL10,CXCL9,CXCL11.Block neovascularization of tumor, recruit macrophages, DCs ,γδ-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 are trafficked to the draining lymph node.;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.;Tumor specific CD4+T and CD8+T cells home to tumor site along a chemokine gradient .;Dunn G,et al.Nature immunology. 2002.3(11):991;肿瘤细胞;肿瘤抗原;肿瘤抗原的加工提呈;肿瘤干细胞;Knutson K, et al. Cancer Immunol Immunother 2005, 54: 721–728; N Engl J Med 2006;355:1253 - 1261.;Cancer stem cell;肿瘤微环境中的免疫稳态失衡;Nature.2005,5:263;;肿瘤微环境中的免疫细胞;TH17 cells in tumour immunity and Immunotherapy. NATuRE REVIEWS | Immunology. doi:10.1038/nri2742;;;;肿瘤微环境中的抑制性成分——Treg细胞;Treg细胞定义;大量的研究报道表明: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。;Treg细胞的作用机制;非小细胞性肺癌（NSCLC）与Treg新亚群;Fig 1;;;;CD8+T细胞在肿瘤免疫中的作用;Gadd45β-/- mice or Het/WT mice were injected into intradermally of flank skin with 2.5X104 B16 cells/mouse.;Fig 4 Gadd45β-/- 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.;5.Bo