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 T细胞和肿瘤之间的相互作用， 对细胞毒性T淋巴细胞（CTL）应答了解甚少。我们 长期目标是获得更基本的理解， 参与T细胞识别肿瘤相关抗原的机制 抗原（TAA），以及随后的肿瘤特异性T细胞应答， 然后可以将其转化为更有效的方法， 细胞免疫疗法肿瘤生长尽管存在 TAA特异性T细胞表明无效的T细胞 识别/激活可能起着关键作用。此外，委员会认为， 大多数已鉴定的TAA是自身蛋白， 这就提出了外周耐受性的问题。我们建议使用 转基因技术和最近分离的MCA肉瘤反应 TCR基因获得了更基本的理解， 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 反应我们的具体目标是：1.1-1.3）创建和表征 转基因小鼠以提供初始肿瘤特异性T细胞，然后 利用TCR转基因骨髓产生T细胞嵌合体。这些 将用肿瘤进行攻击，以确定恶性细胞是否 尽管有足够的T细胞， 前兆频率具体目标2.1-2.3将利用转基因技术 TCR细胞，以1）确定肿瘤是否单独可以有效地 将TAA呈递给初始T细胞，和2）使用过继性T细胞， 转移到同系小鼠中，体内TAA依赖性克隆 肿瘤特异性T细胞的扩增和运输。此外，本发明还 我们将确定CTLA-4阻断在产生一种新的免疫应答中的作用。 有效的CTL应答。最后，具体目标3.1将解决 肿瘤微环境对体内T细胞免疫应答影响 将活化的转基因T细胞转移到荷瘤裸鼠中 小鼠，并评估其随后的细胞因子/活化概况， 局部肿瘤部位。这项建议的主要优点是， 产生初始肿瘤特异性T细胞，使我们能够 解决有关T细胞活化的重要问题， 以简单明了的方式治疗肿瘤。的能力 了解这些基本机制可能会导致更多 有效的癌症治疗形式，并提供新的见解， 肿瘤免疫学原理