CD8+ T Cells and Immunological Tumor Regression

描述(申请人提供)：CD8+T细胞对于免疫性肿瘤排斥反应通常是必不可少的，但由于物理或免疫局部屏障而无法摧毁已建立的实体肿瘤。这个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，使用两种实体肿瘤模型：(I)表达直接和/或间接呈递的抗原LD/SIYRYGL的自发或化学诱导的肿瘤；(Ii)表达HPV癌基因E6/E7的移植或原代实体肿瘤。施赖伯博士将研究并试图对抗局部物理和/或免疫屏障所涉及的机制，这种屏障可能会阻止T细胞启动、记忆发展和吸引T细胞进入实体肿瘤。傅博士将尝试消除启动和吸引原始T细胞进入实体肿瘤的局部障碍，并将试图通过导致实体肿瘤中次级淋巴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受体的配体引入肿瘤来做到这一点。Gajeski博士正在设计方法和程序，以对抗肿瘤微环境或循环中对CD8+T细胞的负面调控影响，方法是设计缺乏负调控受体的T细胞，或通过新腺病毒转导系统将抗凋亡分子引入T细胞，然后用于体内过继转移。Kast博士将与Nishimura博士合作，通过逆转录病毒转导HPV E6/E7特异性T细胞克隆的T细胞受体基因，使正常外周T细胞具有肿瘤特异性，并使用这些改良的T细胞来研究它们在过继转移小鼠已建立的肿瘤和肺转移中的效率。最后，Meredith博士(生物化学核心)和Nishimura博士(分子核心)将就该计划的多个生化和分子方面提供建议和指导，并提供分析和生产必要的试剂，而作为统计核心的一部分，卡里森博士将在建议的实验的进一步设计和评估中提供建议。因此，这三个核心将帮助这四个项目确定CD8+T细胞反应摧毁实体肿瘤的条件和机制。

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.