CD70 mediated costimulation of T cell responses

描述（由申请人提供）：免疫疗法为放疗或化疗耐药肿瘤提供了一种有希望的替代治疗方法，但由于患者的持续成功治疗仍然难以捉摸，因此热情有所降低。我们研究的广泛、长期目标是确定可用于增强肿瘤免疫控制的免疫调节剂。对免疫系统如何成功应对入侵的病原体，却未能阻止肿瘤生长的比较分析，应该提供有关免疫反应激活的重要信息，这些信息可以纳入疫苗设计。通过CD40刺激的树突状细胞变得高度免疫原性，并上调共刺激分子的表达。其中一种分子是CD70，它是TNF细胞因子家族的一员。来自我们实验室的几条证据表明，cd70介导的共刺激为CD8+ T细胞的完全激活提供了一个重要信号，这表明靶向CD27-CD70相互作用的免疫疗法可能导致对肿瘤生长的控制增加。然而，关于CD70在体内的表达调控却知之甚少。我们假设CD70在树突状细胞上的表达在CD40刺激后优先上调，可能还有T细胞，激活的CD4+ T细胞通过提供CD40配体显著地促进了这一过程。为了验证这一假设，并进一步研究靶向这一共刺激途径增强免疫治疗的潜力，我们建议：1)严格定义CD70在树突状细胞和T细胞上的表达模式和表达调控；2)确定DC细胞和T细胞上CD70表达对免疫后T细胞反应发展的相对重要性。从这些研究中获得的结果应该提供对这种共刺激分子如何被调节的见解，并为基于其免疫刺激特性的治疗干预的智能设计提供框架。

DESCRIPTION (provided by applicant): Immune-based therapies offer a promising alternative treatment to radiotherapy- or chemotherapy-resistant tumors, but enthusiasm is tempered by the fact that consistently successful treatment of patients has remained elusive. The broad, long-term objective of our research is to define immune modulators that can be used to enhance the immunological control of tumors. A comparative analysis of how the immune system successfully deals with invading pathogens, yet fails to prevent tumor outgrowth, should provide important information about activation of immune responses that can be incorporated into vaccine design. Dendritic cells that have been stimulated via CD40 become highly immunogenic and upregulate the expression of costimulatory molecules. One such molecule is CD70, a member of the TNF family of cytokines. Several lines of evidence from our laboratory suggest that CD70-mediated costimulation provides an important signal for full activation of CD8+ T cells, indicating that immune therapies that target CD27-CD70 interactions may result in increased control of tumor outgrowth. However, little is known about the regulation of CD70 expression in vivo. We hypothesize that CD70 expression is preferentially upregulated on dendritic cells, and perhaps T cells, after stimulation via CD40, and that activated CD4+ T cells prominently contribute to this process by supplying CD40-ligand. To test this hypothesis and to further the potential of targeting this costimulatory pathway for enhanced immunotherapy, we propose to 1) rigorously define the expression patterns and regulation of expression of CD70 on dendritic cells and T cells in vivo, and 2) determine the relative importance of CD70 expression on DC versus T cells for the development of T cell responses after immunization. The results obtained from these studies should provide insights into how this costimulatory molecule is regulated, and provide a framework for the intelligent design of therapeutic interventions based on its immunostimulatory properties.