CD8+ T cells and Immunological Tumor Regression

描述（由申请人提供）：CD8+ 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：在效应阶段缺乏适当的启动或阻塞。这个项目的重点是代表大多数人类癌症的实体肿瘤。实体肿瘤微环境的局部屏障不仅阻碍了放疗和化疗，也阻碍了CD8+ T细胞介导的肿瘤破坏。这使得这些治疗后癌症复发成为一个常见的问题。临床癌症通常至少含有10A9个癌细胞，其中含有不同数量的癌症干细胞。这些癌细胞在基因上是多样的，期望任何单一的治疗或机制将根除整个癌细胞群似乎是不现实的。因此，这项建议不仅是诱导、恢复和提高CD8+ T细胞的破坏能力，而且是寻找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子的因子，这些先天因子可以导致T细胞成功启动，以应对生长中的肿瘤，特别强调I型干扰素和下游因子，如IL-1，导致CD8+ T细胞交叉启动。项目2将针对已建立实体瘤，远处转移的小鼠，确定瘤内LIGHT治疗联合抗her2 /neu抗体是否可以增加肿瘤细胞凋亡，从而增加CD8+ T细胞启动，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，靶向实体瘤的CD8+ T细胞基质可以防止癌症变体从治疗中逃逸。蛋白表达和肽核心将为上述项目提供所需的蛋白质和肽，而行政/统计/光学成像核心将监督项目，提供统计建议，并允许光学成像实时分析四个项目中提出的操作后肿瘤微环境中发生的事件。CD8+ T细胞可以破坏已建立的实体瘤，但复发很常见。目标是(i)操纵和靶向肿瘤微环境，以克服治疗后的复发；（ii）探索新的免疫学概念和工程试剂，可以与其他新型和传统疗法协同作用。

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.