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CD8+ T cells and Immunological Tumor Regression

CD8 T 细胞和免疫肿瘤消退

基本信息

批准号：
8270396
负责人：
Hans Schreiber
金额：
$ 148.11万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-25 至 2014-05-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：CD 8 + T细胞可以破坏已建立的实体瘤，但复发是常见的。两个主要的速率限制步骤是：缺乏适当的启动或阻断效应相。该计划侧重于代表大多数人类癌症的实体肿瘤。由实体瘤微环境施加的局部屏障不仅阻碍放疗和化疗，还阻碍CD 8 + 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问题。临床癌症通常具有至少10A 9癌细胞，其含有可变数量的癌症干细胞。这些癌细胞在遗传上是多样化的，任何单一疗法或机制都将根除整个癌细胞群体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CD 8 + T细胞的破坏力，而且是为了找到以可预测的协同方式招募额外机制和治疗的策略。项目1将研究介导和定义先天因素的因素，这些因素可以导致T细胞成功启动以应对不断增长的肿瘤，特别强调I型干扰素和下游因子如IL-1，导致CD 8 + T细胞的交叉启动。项目2将靶向具有已建立的实体瘤、远处转移的小鼠，并确定肿瘤内LIGHT治疗与抗Her 2/neu抗体结合是否可以增加肿瘤细胞凋亡，从而增加CD 8 + T细胞引发并改变肿瘤微环境以允许T细胞成熟至完全效应阶段。项目3将研究使用工程化T细胞受体破坏实体瘤的要求和可能的限制。项目4将利用靶向实体瘤间质的CD 8 + T细胞可以防止癌症变体从治疗中逃逸的发现。蛋白质表达和肽核心将提供上述项目所需的蛋白质和肽，而管理/统计/光学成像核心将忽略项目，提供统计建议，并允许在四个项目中提出的操作后对肿瘤微环境中发生的事件进行真实的光学成像分析。CD 8 + T细胞可以破坏已建立的实体瘤，但复发是非常常见的。其目标是（i）操纵和靶向肿瘤微环境，以克服治疗复发，（ii）探索新的免疫学概念和工程试剂，可以与其他新的和传统的疗法协同作用。