T CELL RECOGNITION OF TUMOR ANTIGEN

T 细胞对肿瘤抗原的识别

• 批准号: 2733148
• 负责人: DAVID J COLE
• 金额: $ 10.15万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-21 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2733148
• 关键词: T cell receptor; antigen presentation; athymic mouse; cellular immunity; cytokine; cytotoxic T lymphocyte; flow cytometry; genetically modified animals; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunology; passive immunization; polymerase chain reaction; sarcoma; tumor antigens

T-cells can mediate anti-tumor responses in select patients, but the interaction between T-cells and tumor which can lead to a cytotoxic T-lymphocyte (CTL) response is poorly understood. Our long-range goal is to gain a more fundamental understanding of the mechanisms involved in T-cell recognition of tumor associated antigen (TAA), and the subsequent tumor specific T-cell responses, which can then be translated into more effective approaches to cellular immunotherapy. Growth of tumor despite the existence of TAA specific T-cells suggests that ineffective T-cell recognition/activation may be playing a critical role. Furthermore, the fact that the majority of identified TAA are self proteins raises the question of peripheral tolerance. We propose to use transgenic technology and recently isolated MCA sarcoma reactive TCR genes gain a more fundamental understanding of the possible role of tumor tolerance, the availability/presentation of TAA to naive T-cells, and effects of the local tumor milieu on T-cell response. Our specific aims are: 1.1-1.3) create and characterize transgenic mice to provide naive tumor specific T-cells, and then create a T-cell chimera utilizing TCR transgenic bone marrow. These will be challenged with tumor to determine whether malignant cells will avoid an effective CTL response despite adequate T-cell precursor frequency. Specific aims 2.1-2.3 will utilize transgenic TCR cells to 1) determine whether tumor alone can effectively present TAA to naive T-cells, and 2) define, using adoptive transfer into syngenic mice, the in vivo TAA-dependent clonal expansion and trafficking of tumor specific T-cells. Additionally, we will define the role of CTLA-4 blockade in the generation of an effective CTL response. Finally, specific aim 3.1 will address the effect of tumor micro environment on T-cell response in vivo by transferring activated transgenic T-cells into tumor bearing nude mice and evaluating their subsequent cytokine/activation profile at the local tumor site. The major advantage of this proposal is the creation of naive tumor specific T-cells which enables us to address important questions concerning T-cell activation and response to tumor in a clear and simple manner. The ability to understand these basic mechanisms could potentially lead to more effective forms of therapy for cancer and provide new insight into principles of tumor immunology.

T 细胞可以在特定患者中介导抗肿瘤反应，但是 T 细胞与肿瘤之间的相互作用可导致 人们对细胞毒性 T 淋巴细胞 (CTL) 反应知之甚少。我们的 长期目标是获得对 T细胞识别肿瘤相关的机制 抗原 (TAA)，以及随后的肿瘤特异性 T 细胞反应， 然后可以转化为更有效的方法 细胞免疫疗法。尽管存在肿瘤，但肿瘤仍在生长 TAA 特异性 T 细胞表明无效 T 细胞 识别/激活可能发挥着关键作用。此外， 大多数已识别的 TAA 都是自身蛋白 提出了外周耐受性的问题。我们建议使用 转基因技术与最近分离的MCA肉瘤反应性 TCR 基因对可能的情况有了更基本的了解 肿瘤耐受性的作用、TAA 的可用性/呈现 初始 T 细胞，以及局部肿瘤环境对 T 细胞的影响 回复。我们的具体目标是：1.1-1.3）创造并表征 转基因小鼠提供初始肿瘤特异性 T 细胞，然后 利用 TCR 转基因骨髓创建 T 细胞嵌合体。这些 将受到肿瘤的挑战以确定是否是恶性细胞 尽管有足够的 T 细胞，仍会避免有效的 CTL 反应 前兆频率。具体目标2.1-2.3将利用转基因 TCR细胞1）确定肿瘤单独是否可以有效 将 TAA 呈现给初始 T 细胞，并且 2) 使用过继定义 转移到同基因小鼠中，体内 TAA 依赖性克隆 肿瘤特异性 T 细胞的扩增和运输。此外， 我们将定义 CTLA-4 阻断在生成 有效的CTL反应。最后，具体目标 3.1 将解决 肿瘤微环境对体内T细胞反应的影响 将激活的转基因T细胞转移到荷瘤裸体内 小鼠并评估其随后的细胞因子/激活谱 局部肿瘤部位。该提案的主要优点是 创建初始肿瘤特异性 T 细胞，使我们能够 解决有关 T 细胞激活的重要问题 以清晰简单的方式应对肿瘤。有能力 了解这些基本机制可能会带来更多 癌症的有效治疗形式并提供新的见解 肿瘤免疫学原理。