CD8+ T cells and Immunological Tumor Regression

描述(申请人提供)：CD8+T细胞可以摧毁已建立的实体瘤，但复发是常见的。两个主要的速率限制步骤是：在效应器阶段缺乏适当的启动或阻塞。这个项目关注的是占人类癌症大多数的实体肿瘤。实体肿瘤微环境造成的局部屏障不仅阻碍放化疗，而且阻碍CD8+T细胞介导的肿瘤破坏。这使得这些治疗后的癌症复发成为一个常见的问题。临床癌症通常至少含有10A9癌细胞，其中含有数量可变的癌症干细胞。这些癌细胞在基因上是多样化的，任何单一的治疗方法或机制都能根除整个癌细胞的期望似乎是不现实的。因此，这一建议不仅是为了诱导、恢复和提高CD8+T细胞的破坏力，而且是为了寻找策略，以可预见的协同方式招募额外的机制和治疗方法。项目1将研究调节和定义先天因素的因素，这些先天因素可以导致在肿瘤生长时成功地启动T细胞，特别强调I型干扰素和下游因素，如导致CD8+T细胞交叉启动的IL-1。项目2将针对已有实体瘤和远处转移的小鼠，并确定瘤内光治疗与抗Her2/neu抗体联合使用是否可以增加肿瘤细胞的凋亡，从而增加CD8+T细胞的启动，并改变肿瘤微环境，使T细胞成熟到完全效应阶段。项目3将研究使用工程化T细胞受体来破坏实体肿瘤的要求和可能的限制。项目4将利用这一发现，即靶向实体肿瘤间质的CD8+T细胞可以防止癌症变异体逃脱治疗。蛋白质表达和多肽核心将提供上述项目所需的蛋白质和多肽，而行政/统计/光学成像核心将忽略这些项目，提供统计建议，并允许光学成像分析在四个项目提出的操作后在肿瘤微环境中发生的事件。CD8+T细胞可以摧毁已建立的实体肿瘤，但复发非常常见。其目标是(I)操纵和靶向肿瘤微环境，以克服治疗中的复发，以及(Ii)探索新的免疫学概念和工程试剂，以与其他新的和传统的治疗方法协同。

DESCRIPTION (provided by applicant): CD8+ T cells can destroy established solid tumors, but relapse is common. Two major rate limiting steps are: lack of proper priming or block in the effector phase. This program focusses on solid tumors that represent the majority of human cancers. Local barriers imposed by the solid tumor microenvironment not only impede radiation and chemotherapy but also CD8+ T cell-mediated tumor destruction. This makes cancer recurrence after these therapies a common problem. Clinical cancers usually harbor at least 10A9 cancer cells containing a variable number of cancer stem cells. These cancer cells are genetically diverse, and the expectation that any single therapy or mechanism will eradicate the entire population of cancer cells seems unrealistic. Therefore, this proposal is not only to induce, restore and improve destructive power of CD8+ T cells, but to find strategies for enlisting additional mechanisms and treatments in a predictably synergistic way. Project 1 will study the factors that will mediate and define innate factors that can lead to successful T cell priming in response to a growing tumor with particular emphasis on type I interferons and downstream factors like IL-1 leading to cross-priming of CD8+ T cells. Project 2 will target mice with established solid tumors, distant metastases and determine whether intratumoral LIGHT treatment in conjunction with anti-Her2/neu antibody can increase tumor cell apoptosis and thereby increase CD8+ T cell priming and alter the tumor microenvironment to allow T cell maturation to a full effector stage. Project 3 will study the requirements and possible limitations of using engineered T cell receptors for the destruction of solid tumors. Project 4 will exploit the finding that targeting the stroma of solid tumors CD8+ T cells can prevent escape of cancer variants from therapy. The Protein Expression and Peptide Core will provide the proteins and peptides needed for the above projects, while the Administrative/Statistics/Optical Imaging Core will overlook the projects, give statistical advice and allow optical imaging analysis in real time of the events occurring in the tumor microenvironment following manipulations proposed in the four projects. CD8+ T cells can destroy well-established solid tumors but relapse is very common. The goal is to (i) manipulate and target the tumor microenvironment to overcome recurrence from therapy and (ii) explore novel immunological concepts and engineered reagents that can synergize with other novel as well as conventional therapies.