CD8+ T Cells and Immunological Tumor Regression

CD8 T 细胞和免疫肿瘤消退

• 批准号: 6900349
• 负责人: Hans Schreiber
• 金额: $ 151.21万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-25 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6900349
• 关键词: cellular immunity; clinical research; cytotoxic T lymphocyte; immune tolerance /unresponsiveness; immunoregulation; neoplasm /cancer immunology; neoplasm /cancer remission /regression

DESCRIPTION (provided by applicant): CD8+ T cells are often essential for immunological tumor rejection but fail to destroy established solid tumors because of a physical or immunological local barrier. The common goal of this project is to understand and overcome the failure of CD8+ T cells to destroy established tumors. In principle, two solid tumor models are being used: (i) spontaneous or chemically induced tumors expressing the directly and/or indirectly presented antigen Ld/SIYRYYGL and (ii) transplanted or primary solid tumors that express the oncogene E6/E7 of HPV. Dr. Schreiber will study - and attempt to counteract - the mechanisms involved in the local physical and/or immunological barrier that may prevent the priming, memory development and attraction of T cells into solid tumors. Dr. Fu will attempt to eliminate the local barrier to priming and attraction of nave T cells into solid tumors, and he will attempt to improve the entry and proliferation of memory T cells by causing the development of secondary lymphoid structures in solid tumors. He plans to do this by introducing ligands for the lymphotoxin Beta-receptor into the tumor. Dr. Gajewski is devising means and procedures to counter negative regulatory influences on CD8+ T cells occurring in the tumor microenvironment or the circulation by devising T cells that lack negative regulatory receptors or by introducing with a novel adenoviral transduction system anti-apoptotic molecules into T cells that then will be used for adoptive transfer in vivo. Dr. Kast in collaboration with Dr. Nishimura will make normal peripheral T cells tumor-specific by retroviral transduction with T cell receptor genes of HPV E6/E7 specific T cell clones and use these modified T cells to study their efficiency in adoptive transfer on established tumors and lung metastases in mice. Finally, Dr. Meredith (Biochemistry Core) and Dr. Nishimura (Molecular Core) will give advice and guidance on the multiple biochemical and molecular aspects of the program, and provide assays and produce essential reagents, while Dr. Karrison as part of the Statistics Core will give advice in further design and evaluation of the proposed experiments. Thus, the three cores will help the four projects to define conditions and mechanisms by which CD8+ T cell responses can destroy solid established tumors.

描述（由申请人提供）：CD8+ T细胞通常对于免疫学肿瘤排斥而言至关重要，但由于物理或免疫学局部障碍而无法破坏已建立的实体瘤。 该项目的共同目标是了解和克服CD8+ T细胞破坏已建立的肿瘤的失败。 原则上，正在使用两个实体瘤模型：（i）自发或化学诱导的肿瘤，表达直接和/或间接呈现的抗原LD/siyryygl和（ii）表达HPV的癌基因E6/E7的移植或原发性实体瘤。 Schreiber博士将研究并试图抵消 - 局部物理和/或免疫障碍中涉及的机制，这些机制可能会阻止T细胞启动，记忆发展和吸引到实体瘤中。 FU博士将试图消除Na Ve T细胞启动和吸引到实体瘤的局部障碍，他将尝试通过导致实体瘤中二级淋巴样结构的发展来改善记忆T细胞的进入和增殖。 他计划通过将淋巴毒素β受体受体的配体引入肿瘤来做到这一点。 Gajewski博士正在制定手段和程序，以应对对肿瘤微环境中发生的CD8+ T细胞的负面影响，或者通过设计缺乏负调节受体的T细胞或通过引入新型腺病毒转导系统抗磷酸化细胞的T细胞，然后将其引入，然后将其用于接收性转移的T细胞中，该细胞将用于接收性转移。 KAST博士与Nishimura博士合作，将通过逆转录病毒特异性与HPV E6/E7特异性T细胞克隆的T细胞受体基因逆转录转导肿瘤特异性，并使用这些修饰的T细胞研究其在小鼠中已建立的肿瘤和肺转移酶的收养效率。最后，Meredith博士（生物化学核心）和Nishimura博士（Molecular Core）将对该程序的多个生物化学和分子方面提供建议和指导，并提供测定并生产基本试剂，而Karrison博士作为统计数据的一部分，将在进一步的设计和评估建议实验方面提供建议。因此，这三个核心将帮助四个项目定义CD8+ T细胞反应可以破坏固体肿瘤的条件和机制。