Tumor Gangliosides and TNF Synergize for T Cell Death

肿瘤神经节苷脂和 TNF 协同作用导致 T 细胞死亡

• 批准号: 6854965
• 负责人: CHARLES S. TANNENBAUM
• 金额: $ 27.2万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6854965
• 关键词: T lymphocyte; apoptosis; biological signal transduction; cell line; cell membrane; clinical research; gangliosides; high performance liquid chromatography; human subject; lipids; mitochondria; neoplasm /cancer immunology; nuclear factor kappa beta; renal cell carcinoma; terminal nick end labeling; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): While there is growing evidence for tumor-associated antigens in renal cell carcinoma (RCC), most spontaneous immune responses to the disease are ineffective at limiting tumor progression. One mechanism by which tumors promote their own progressive growth is by inducing or sensitizing T cells to apoptosis. We recently determined that the ability of several RCC cell lines to mediate significant levels of apoptosis in co-cultured T cells is largely abrogated when the co-incubations are performed either in the presence of neutralizing anti-TNF antibodies, or with ganglioside-depleted tumor cells. This suggestion of a synergistic effect between tumor-derived gangliosides and TNF for inducing T cell apoptosis is corroborated by studies with purified sources of TNF and the RCC-overexpressed ganglioside GM1, which demonstrate similar cooperativity for killing T cells when used together in vitro. Our previous work indicated that select gangliosides can inhibit NFkappaB activation in T cells, thereby sensitizing the lymphocytes to apoptosis by preventing their synthesis of NFkappaB-dependent, anti-apoptotic proteins. The mechanism by which gangliosides cause that defect, and the nature of the second signal actually inducing apoptosis, however, have remained undefined. Preliminary data now suggest that RCC-derived gangliosides and TNF synergize to induce T cell apoptosis by two different mechanisms. We hypothesize that tumor-derived gangliosides disrupt lipid rafts on T cell membranes, preventing effective NFkappaB activation through TNFR1, and hence rendering apoptosis the default pathway induced upon TNF binding. We also have evidence that TNF enhances the effectiveness with which RCC gangliosides induce proapoptotic effects on the mitochondrion, accelerating the onset and intensity of the ROS and MPT mediated by gangliosides alone. The experiments outlined in this proposal will both assess the importance of a TNF/ganglioside synergy to RCC-induced T cell apoptosis, and test our hypothesis that both of the proposed, synergistic mechanisms may be contributing to the T cell dysfunction in RCC.

描述（由申请人提供）：虽然越来越多的证据表明肾细胞癌（RCC）中存在肿瘤相关抗原，但大多数对该疾病的自发免疫反应对于限制肿瘤进展无效。肿瘤促进自身进行性生长的一种机制是诱导 T 细胞凋亡或使其敏感。我们最近确定，当在中和性抗 TNF 抗体存在或与神经节苷脂耗尽的肿瘤细胞存在的情况下进行共培养时，几种 RCC 细胞系介导共培养 T 细胞中显着水平的细胞凋亡的能力在很大程度上被消除。肿瘤源性神经节苷脂和 TNF 之间对诱导 T 细胞凋亡具有协同作用，这一点得到了纯化来源的 TNF 和 RCC 过表达神经节苷脂 GM1 的研究的证实，这些研究表明，在体外一起使用时，在杀死 T 细胞方面具有相似的协同作用。我们之前的工作表明，选择的神经节苷脂可以抑制 T 细胞中 NFkappaB 的激活，从而通过阻止淋巴细胞合成 NFkappaB 依赖性抗凋亡蛋白来使淋巴细胞对细胞凋亡敏感。然而，神经节苷脂引起该缺陷的机制以及实际上诱导细胞凋亡的第二信号的性质仍然不清楚。现在的初步数据表明，RCC 衍生的神经节苷脂和 TNF 通过两种不同的机制协同诱导 T 细胞凋亡。我们假设肿瘤源性神经节苷脂会破坏 T 细胞膜上的脂筏，阻止 TNFR1 有效激活 NFkappaB，从而使细胞凋亡成为 TNF 结合诱导的默认途径。我们还有证据表明，TNF 增强了 RCC 神经节苷脂诱导线粒体促凋亡作用的有效性，加速了仅由神经节苷脂介导的 ROS 和 MPT 的发生和强度。本提案中概述的实验将评估 TNF/神经节苷脂协同作用对 RCC 诱导的 T 细胞凋亡的重要性，并检验我们的假设，即所提出的两种协同机制可能导致 RCC 中的 T 细胞功能障碍。