CD8+ T cells and Immunological Tumor Regression

CD8 T 细胞和免疫肿瘤消退

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8270396
• 关键词: Antibodies; Apoptosis; CD8B1 gene; Cell Maturation; Clinical; Cross-Priming; Distant Metastasis; ERBB2 gene; Engineering; Event; Goals; Human; Image Analysis; Interferon Type I; Interleukin-1; Lead; Light; Malignant Neoplasms; Mediating; Mus; Peptides; Phase; Population; Proteins; Radiation; Reagent; Recurrence; Relapse; Solid Neoplasm; Staging; T-Cell Receptor; T-Lymphocyte; Time; Variant; cancer cell; cancer recurrence; cancer stem cell; chemotherapy; conventional therapy; expectation; improved; neoplastic cell; novel; optical imaging; prevent; programs; protein expression; response; statistics; tumor

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）：CD8+ T细胞可以破坏已建立的实体瘤，但复发很常见。两个主要的限制步骤是：在效应子阶段缺乏适当的启动或阻塞。该计划的重点是代表大多数人类癌症的实体瘤。实体瘤微环境施加的局部障碍不仅阻碍了放射疗法和化学疗法，还阻碍了CD8+ T细胞介导的肿瘤破坏。这会使这些疗法后的癌症复发成为常见问题。临床癌症通常至少含有含有癌症干细胞数量可变的癌细胞。这些癌细胞在遗传上是多种多样的，并且期望任何一种单一的治疗或机制都会消除整个癌细胞群体似乎是不现实的。因此，该建议不仅是为了诱导，恢复和改善CD8+ T细胞的破坏力，而且要以可预测的协同方式寻找其他机制和处理的策略。项目1将研究介导和定义先天因素的因素，这些因素可能导致成功的T细胞启动，以响应增长的肿瘤，特别着重于I型干扰素和下游因素，例如IL-1导致CD8+ T细胞的交叉染色。项目2将以既定的实体瘤，远处转移的态度靶向小鼠，并确定肿瘤内光治疗与抗HER2/NEU抗体是否可以增加肿瘤细胞凋亡，从而增加CD8+ T细胞启动并改变肿瘤微环境，从而使T细胞成熟到全部效应阶段。项目3将研究使用工程T细胞受体破坏实体瘤的要求和可能的局限性。项目4将利用以下发现，即针对实体瘤CD8+ T细胞的基质可以防止癌症变异的治疗。蛋白质表达和肽核将提供上述项目所需的蛋白质和肽，而行政/统计/光学成像核心将忽略项目，提供统计建议并实时允许光学成像分析在四个项目中提出的肿瘤微环境中发生的事件的实时实时。 CD8+ T细胞可以破坏良好的实体瘤，但复发非常普遍。目的是（i）操纵和靶向肿瘤微环境，以克服治疗中的复发，（ii）探索新型免疫学概念和工程试剂，这些试剂可以与其他新型和常规疗法协同作用。

项目成果

Ribosomal versus non-ribosomal cellular antigens: factors determining efficiency of indirect presentation to CD4+ T cells.

核糖体与非核糖体细胞抗原：决定间接呈递至 CD4 T 细胞的效率的因素。

• DOI: 10.1111/j.1365-2567.2010.03258.x
• 发表时间: 2010
• 期刊: Immunology
• 影响因子: 6.4
• 作者: Philip,Mary;Schietinger,Andrea;Schreiber,Hans
• 通讯作者: Schreiber,Hans

Adaptive Immune Responses and HER2/neu Positive Breast Cancer.

适应性免疫反应和 HER2/neu 阳性乳腺癌。

• DOI: 10.1007/s40139-012-0001-8
• 发表时间: 2013-03
• 期刊: Current pathobiology reports
• 作者: Mortenson ED;Fu YX
• 通讯作者: Fu YX

Activation of tolerogenic dendritic cells in the tumor draining lymph nodes by CD8+ T cells engineered to express CD40 ligand.

通过设计表达 CD40 配体的 CD8+ T 细胞激活肿瘤引流淋巴结中的耐受性树突状细胞。

• DOI: 10.4049/jimmunol.0903111
• 发表时间: 2010-04-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Higham EM;Wittrup KD;Chen J
• 通讯作者: Chen J

STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors.

• DOI: 10.1016/j.immuni.2014.10.017
• 发表时间: 2014-11-20
• 期刊: IMMUNITY
• 影响因子: 32.4
• 作者: Woo, Seng-Ryong;Fuertes, Mercedes B.;Corrales, Leticia;Spranger, Stefani;Furdyna, Michael J.;Leung, Michael Y. K.;Duggan, Ryan;Wang, Ying;Barber, Glen N.;Fitzgerald, Katherine A.;Alegre, Maria-Luisa;Gajewski, Thomas F.
• 通讯作者: Gajewski, Thomas F.

Bystander killing of cancer requires the cooperation of CD4(+) and CD8(+) T cells during the effector phase.

• DOI: 10.1084/jem.20092450
• 发表时间: 2010-10-25
• 期刊: The Journal of experimental medicine
• 作者: Schietinger A;Philip M;Liu RB;Schreiber K;Schreiber H
• 通讯作者: Schreiber H