Regulation of Cross-Tolerance to Tumor Antigens

肿瘤抗原交叉耐受的调节

• 批准号: 6858677
• 负责人: EDUARDO M. SOTOMAYOR
• 金额: $ 29.01万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858677
• 关键词: T cell receptor; T lymphocyte; antigen presenting cell; biological signal transduction; bone marrow; cell differentiation; enzyme activity; flow cytometry; genetically modified animals; guanosinetriphosphatases; helper T lymphocyte; immune tolerance /unresponsiveness; laboratory mouse; neoplasm /cancer immunology; neoplastic cell; protein tyrosine kinase; transcription factor; tumor antigens

DESCRIPTION (provided by applicant): Self-antigens represent the most relevant and abundant antigens to which the host's immune system must be tolerant. Induction and maintenance of tolerance to self-antigens is mediated by several mechanisms that prevent inappropriate damage to normal tissues. One mechanism that has gained significant attention in recent years relates to the critical role that bone marrow-derived antigen-presenting cells (APCs) play in the induction of tolerance to self-antigens. This emerging role of APCs in immune tolerance has been recently extended into the field of tumor immunology with the demonstration -as described in detail in this application- that tumor antigen processing and presentation by host's APCs also represents the dominant mechanism mediating tolerance to tumor antigens ("cross-tolerance"). The requirement for bone marrow derived APCs in both the induction of antigen-specific T-cell tolerance as well as in priming effective T-cell antitumor responses, places APCs at the center of a critical decision leading to immune activation versus immune tolerance. Although emerging evidence points to the state of activation and/or differentiation of the APC as the central determinant of T-cell priming versus tolerance, the signaling and molecular mechanism(s) involved in this critical decision remain to be elucidated. Therefore, in this proposal we will utilize a well-characterized model of tumor-induced antigen-specific T-cell tolerance to evaluate the role of Signal Transducer and Activator of Transcription-3 (Stat3), c-kit and mevalonate signaling pathways in the decision -at the APC level- leading to either tolerance or priming of antigen-specific T-cells. In addition, we will explore whether cross-tolerance to tumor antigens can be either prevented and/or reverted by strategies that target these intracellular signaling pathways in APCs.

描述（由申请人提供）：自身抗原代表宿主免疫系统必须耐受的最相关且最丰富的抗原。对自身抗原的耐受性的诱导和维持是由多种机制介导的，这些机制可防止对正常组织的不当损伤。近年来引起广泛关注的一种机制与骨髓源性抗原呈递细胞（APC）在诱导对自身抗原的耐受性中发挥的关键作用有关。 APC 在免疫耐受中的这种新兴作用最近已扩展到肿瘤免疫学领域，正如本申请中详细描述的那样，宿主 APC 的肿瘤抗原加工和呈递也代表了介导对肿瘤抗原耐受的主要机制。 “交叉耐受”）。诱导抗原特异性 T 细胞耐受以及启动有效的 T 细胞抗肿瘤反应都需要骨髓来源的 APC，这使得 APC 处于导致免疫激活与免疫耐受的关键决策的中心。尽管新出现的证据表明 APC 的激活和/或分化状态是 T 细胞启动与耐受的核心决定因素，但参与这一关键决定的信号传导和分子机制仍有待阐明。因此，在本提案中，我们将利用肿瘤诱导的抗原特异性 T 细胞耐受的良好表征模型来评估信号转导器和转录激活剂 3 (Stat3)、c-kit 和甲羟戊酸信号通路在肿瘤细胞中的作用。 APC 水平的决定导致抗原特异性 T 细胞的耐受或启动。此外，我们将探讨是否可以通过针对 APC 中这些细胞内信号通路的策略来预防和/或恢复对肿瘤抗原的交叉耐受。