Tumor Induced Dysregulation of T Cell Immunity

肿瘤诱导的 T 细胞免疫失调

• 批准号: 7232399
• 负责人: JAMES H FINKE
• 金额: $ 26.18万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-12 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7232399
• 关键词: Acetylcysteine; Antigen-Presenting Cells; Antioxidants; Apoptosis; Apoptotic; Binding; CD4 Positive T Lymphocytes; Cancer Patient; Cell Death; Cell Survival; Cell membrane; Cells; Ceramides; Coculture Techniques; Data; Deferoxamine; Development; Disease; Disease Progression; Environment; Event; Excision; Flow Cytometry; Fractionation; Functional disorder; G(M2) Ganglioside; Gangliosides; Generations; High Pressure Liquid Chromatography; Humoral Immunities; Immune; Immune System Diseases; Immune response; Immunity; Immunosuppression; Immunotherapy; In Situ; In Situ Nick-End Labeling; In Vitro; Influenza; Interleukin-10; Interleukin-4; Interleukin-5; Iron; Laboratories; Lysosomes; Mass Spectrum Analysis; Mediating; Membrane Microdomains; Mitochondria; Modeling; Mus; Necrosis; Operative Surgical Procedures; Oxidative Stress; Pathway interactions; Patients; Peptides; Permeability; Plasma; Play; Population; Primary Neoplasm; Process; Reactive Oxygen Species; Renal Cell Carcinoma; Research Personnel; Role; Staging; Staining method; Stains; T-Lymphocyte; Testing; Th1 Cells; Therapeutic immunosuppression; Tissues; Tonsil; Tumor Antigens; Tumor Immunity; Tumor Tissue; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Vaccines; Variant; base; cell killing; cytokine; enzyme linked immunospot assay; migration; peripheral blood; prevent; programs; research study; response; tumor; tumor growth

DESCRIPTION (provided by applicant): Mounting evidence suggests that the tumor environment can inhibit the development of an effective immune response by promoting T cell dysfunction. Studies from our laboratory and several others suggest that the ability of tumors and their products to promote T cell death represents an important mechanism of immune dysfunction. Flow cytometry analysis of tumor infiltrating T cells stained with AnnexinV/7AAD as well as in situ TUNEL staining revealed that a high percentage of these cells showed signs of apoptosis/necrosis, suggesting that the tumor microenvironment has a deleterious effect on tumor infiltrating T cells (TILs), although the immunosuppressive effects of RCC extend into the periphery as well. Additional studies demonstrated that in patients with active disease the T cell response to MAGE-6 and EphA2, expressed by renal cell carcinomas was predominately Type-2 (IL-4, IL-5.IL-10) rather than a type-1(IFNg) which is known to be critical for the development of effective anti-tumor immunity. However, patients rendered disease free by surgery displayed Th-1 responses (IFNg, ELISPOT). HLA-DR4/tumor peptide tetramer studies showed that the MAGE-6 and EphA2 specific CD4+T cells were highly sensitive to apoptosis compared to T cells binding influenza peptides and the bulk peripheral blood T cell population. Our data also suggest that gangliosides play in important role in tumor-induced immune dysfunction. Gangliosides constitute over 50% of the apoptotic activity induced by supernatants from RCC explants and by RCC lines. RCC derived gangliosides can also induce a Th2 bias in vitro. HPLC with on line mass spectrometry analysis suggests that there are several gangliosides, including GM2, which mediate the immunosuppression. Here we plan to determine which of the common gangliosides derived from RCC tissue, supernatant and plasma are the most effective at inducing T cell death, a Type-2 bias, and whether the bias is related to the apoptosis of the MAGE-6 and EphA2 specific Th-1 T cells. We will also determine whether the immune suppression is mediated by select gangliosides shedding from tumor and associating with lipid rafts on the plasma membranes of T cells and whether expression of the inhibitory gangliosides correlates with the Th-2 bias and increased sensitivity of patient T cells to apoptosis (aim1). Whether T cell death induced by ganglosides results from degradation to ceramide or to their migration to mitochondria will be examined (aim2). The observation that the anti-oxidant deferoxamine (DFO) can block ganglioside-mediated apoptosis of T cells will be studied further to define how DFO protects T cells from apoptosis. We will also define the sequence of events leading to T cell death, including the role of iron and lysosomes in this process (aim 3)

描述（由申请人提供）：越来越多的证据表明，肿瘤环境可以通过促进T细胞功能障碍来抑制有效的免疫反应的发展。我们实验室和其他一些人的研究表明，肿瘤及其产物促进T细胞死亡的能力是免疫功能障碍的重要机制。用膜剂/7AAD以及原位TUNEL染色染色的肿瘤浸润的T细胞的流式细胞仪分析表明，这些细胞中的高百分比显示出凋亡/坏死的迹象，这表明肿瘤微环境对肿瘤炎性T细胞具有有害作用，虽然对肿瘤的TIL（TILS）有害效应（TILS），但仍延伸了perim cancccccccccy的效果。其他研究表明，在活性疾病的患者中，由肾细胞癌表示的T细胞对MAGE-6和EPHA2的反应主要是2型（IL-4，IL-5.IL-10），而不是1型1型（IFNG），这对于有效抗肿瘤免疫的发展至关重要。但是，通过手术使疾病不含疾病的患者显示出TH-1反应（IFNG，ELISPOT）。 HLA-DR4/肿瘤肽四聚体研究表明，与结合T细胞结合流感肽和大量的外周血T细胞群，MAGE-6和EPHA2特异性CD4+T细胞对凋亡高度敏感。我们的数据还表明，神经节在肿瘤诱导的免疫功能障碍中起着重要作用。 Gangliosides构成了RCC Epplants和RCC线的上清液引起的凋亡活性的50％以上。 RCC衍生的神经苷也可以在体外诱导Th2偏置。具有线质谱分析的HPLC表明，有几种神经节剂，包括GM2，可以介导免疫抑制。在这里，我们计划确定从RCC组织，上清液和血浆衍生出的常见神经节苷脂最有效地诱导T细胞死亡，一种2型偏置，以及偏见是否与MAGE-6和EPHA2特异性TH-1 T细胞的凋亡有关。我们还将确定免疫抑制是否是通过从肿瘤中脱落的神经节剂介导的，并与T细胞的质膜上的脂质筏相关，以及抑制性神经节剂的表达是否与Th-2偏置和患者T细胞的敏感性相关，患者T细胞与凋亡的敏感性增加（AIM1）。是由神经苷诱导的T细胞死亡导致降解对神经酰胺的降解还是将其迁移到线粒体的迁移（AIM2）。将进一步研究神经节苷脂介导的T细胞凋亡的抗氧化剂脱氧胺（DFO）的观察结果将进一步研究，以定义DFO如何保护T细胞免受凋亡的影响。我们还将定义导致T细胞死亡的事件的顺序，包括铁和溶酶体在此过程中的作用（AIM 3）