Regulation of Cross-Tolerance to Tumor Antigens

肿瘤抗原交叉耐受的调节

• 批准号: 7186746
• 负责人: EDUARDO M. SOTOMAYOR
• 金额: $ 27.51万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7186746
• 关键词: Address; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Antitumor Response; Attention; Autoantigens; B-Cell Lymphomas; Bone Marrow; CD4 Positive T Lymphocytes; Cancer Vaccines; Cell physiology; Cells; Characteristics; Goals; Guanosine Triphosphate Phosphohydrolases; Immune; Immune Tolerance; Immune system; Lymphoid; Maintenance; Malignant Epithelial Cell; Mediating; Modeling; Molecular; Mus; Normal tissue morphology; Numbers; Organ; Outcome; Pathway interactions; Peripheral; Play; Proto-Oncogene Protein c-kit; Regulation; Renal Cell Carcinoma; Research Personnel; Role; STAT3 gene; Signal Pathway; Signal Transduction; Stat3 protein; T-Lymphocyte; Tissues; Tumor Antigens; Tyrosine Kinase Inhibitor; base; functional restoration; hematopoietic tissue; in vivo; mevalonate; neoplastic cell; novel strategies; prevent; programs; response; tumor; tumor immunology; vaccine efficacy

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.

说明(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和最丰富的抗原。诱导和维持对自身抗原的耐受性是通过几种机制来调节的，这些机制可以防止对正常组织的不适当损害。近年来备受关注的一种机制与骨髓来源的抗原提呈细胞(APC)在诱导自身抗原耐受中所起的关键作用有关。APC在免疫耐受中的这一新兴作用最近已扩展到肿瘤免疫学领域，如本申请中详细描述的那样，宿主APC对肿瘤抗原的处理和递送也代表了介导对肿瘤抗原的耐受(交叉耐受)的主要机制。在诱导抗原特异性T细胞耐受以及启动有效的T细胞抗肿瘤反应方面，对骨髓来源的APC的要求将APC置于导致免疫激活与免疫耐受的关键决策的中心。尽管新的证据表明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和分子机制(S)仍有待阐明。因此，在这项建议中，我们将利用肿瘤诱导的抗原特异性T细胞耐受模型来评估信号转导和转录激活因子-3(STAT3)、c-kit和甲羟戊酸信号通路在APC水平上导致抗原特异性T细胞耐受或启动的决策中的作用。此外，我们还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/或逆转对肿瘤抗原的交叉耐受。