Memory T Cells in the Tumor Microenvironment

肿瘤微环境中的记忆T细胞

基本信息

批准号：
8119169
负责人：
WEIPING ZOU
金额：
$ 39.3万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8119169
关键词：
ABCG2 gene Address Antigen-Presenting Cells Antigens CD4 Positive T Lymphocytes CD8B1 gene Cancer cell line Cells Cellular biology Chromatin Chromatin Structure Chronic Clinical Complex Data Dendritic Cells Embryo Embryonic Development Epigenetic Process Ethics Exhibits Fibroblasts Gene Cluster Gene Expression Gene Targeting Generations Genes Genetic Goals Growth Health Histone H3 Histones Human Immune Immune system Immunity Immunotherapy Infection Knowledge Life Link Longevity Maintenance Malignant Neoplasms Malignant neoplasm of ovary Mediating Mediator of activation protein Memory Methods Methylation Mus Nature Pathogenesis Pathway interactions Patients Pattern Phenotype Play Polycomb Property Proteins Regulation Research Role Stem cells T memory cell T-Lymphocyte T-Lymphocyte Subsets Testing Transfusion Tumor Immunity Vaccination Work adaptive immunity arm blastomere structure cancer cell cancer stem cell comparative gene repression genetic profiling histone methyltransferase human EZH2 protein infectious disease model insight novel novel strategies pathogen response senescence stem stem cell division stemness tumor

项目摘要

DESCRIPTION (provided by applicant): Memory CD8+ T cells are one of the most important players in mediating protective tumor immunity. The major goal of tumor immune therapy and immune vaccination including adoptive effector T cell and dendritic cell transfusion is to engender long-term protective memory CD8+ T cell immunity, and in turn results in tumor eradiation in patients with cancer. However, our current knowledge of memory T cells arises almost exclusively from studies of infectious disease models. The induction of memory T cells in cancer is often inadvertently thought of as being analogous to that observed in chronic infections. It is evident that the generation and function of memory T cells are dramatically impacted by the tumor microenvironment. We recently performed preliminary studies on the phenotype, functionality and epigenetic of memory CD8+ T cell subsets in human tumors. We have observed multiple phenotypically and functionally distinct memory CD8+ T cell subsets in ovarian cancer microenvironment. A number of unique clusters of genes were identified along with these memory CD8+ T cell subsets. Among these genes, the expression patterns of the polycomb group (PcG) protein like Enhancer of zeste homolog 2 (Ezh2), Ezh2-dependent trimethylation gene H3K27 (H3K27me3) and the target genes like Ezh2/Ink4a/Arf pathway are associated with particular CD8+ memory T cell subsets. Recent studies have revealed that Ezh2-dependent H3K27 trimethylation (H3K27me3) represses target genes like Ink4a/Arf to control growth, survival and renewal of cancer cells, cancer stem cells, ¿ cells and embryonic fibroblasts. However, the expression, regulation and role of Ezh2/Ink4a/Arf pathway have not been explored in immune cells including humans and mice. Our work suggests that epigenetic regulation plays a role in controlling memory T cell "stemness" (proliferation, renewal and survival) and effector function of CD8+ memory T cell subsets in the tumor. Our specific aims are: Aim 1 is to test our hypothesis that ABCG2+CD8+ memory T cells exhibit the stem-like properties (stemness) in the OC microenvironment. Aim 2 is to test our hypothesis that distinct epigenetic histone profiles are linked to specific CD8+ memory T cell subsets in the OC microenvironment. Aim 3 is to test our hypothesis that the Ezh2/Ink4a/Arf pathway importantly determines the fate of CD8+ memory T cells, and that reprogramming this pathway engenders potent long-term anti-tumor immunity. PUBLIC HEALTH RELEVANCE: Our understanding of memory CD8+ T cells in human tumor microenvironment lags much behind the more comprehensive analyses of these cells in infectious disease models. This deficiency significantly tempers our efforts toward understanding basic human memory T cell biology and potential application. The application takes a comprehensive approach by combining basic immunological methods, genetic and epigenetic research, and clinical and comparative analyses to address the nature of memory CD8+ T cells in the human tumor microenvironment. The application is conceptually and applicably significant, and will generate novel insight into new approaches in cancer immune therapy and vaccination.

描述（由适用提供）：记忆CD8+ T细胞是介导受保护肿瘤免疫史的最重要的参与者之一。肿瘤免疫疗法和免疫疫苗（包括适应性效应T细胞和树突状细胞输血）的主要目标是导致长期保护记忆CD8+ T细胞免疫史，进而导致癌症患者的肿瘤警报。但是，我们目前对记忆T细胞的了解几乎完全来自对传染病模型的研究。癌症中记忆T细胞的诱导通常被无意间认为是类似于在慢性感染中观察到的类似。有证据表明记忆T细胞的产生和功能受到肿瘤微环境的巨大影响。我们最近对人肿瘤中记忆CD8+ T细胞亚群的表型，功能和表观遗传学进行了初步研究。我们已经在卵巢癌微环境中观察到了多个表型和功能上不同的记忆CD8+ T细胞子集。确定了许多独特的基因簇以及这些记忆CD8+ T细胞子集。在这些基因中，PolyComb组（PCG）蛋白的表达模式（如Zeste同源物2（EZH2）的增强子，EZH2依赖性三甲基化基因H3K27（H3K27ME3）和诸如EZH2/INK4A/ARF途径（例如EZH2/ARF PATH）之类的靶基因与特定的CD8+ CD8+记忆T分类相关联。最近的研究表明，EZH2依赖性H3K27三甲基化（H3K27ME3）代表诸如Ink4a/ARF之类的靶基因，以控制癌细胞，癌细胞，细胞，细胞和胚胎成纤维细胞的生长，生存和更新。然而，在包括人类和小鼠在内的免疫细胞中尚未探索EZH2/INK4A/ARF途径的表达，调节和作用。我们的工作表明，表观遗传调节在控制记忆T细胞“ Stemness”（增殖，更新和存活）和肿瘤中CD8+记忆T细胞亚群的效应函数中起作用。我们的具体目的是：目标1是测试我们的假设，即ABCG2+ CD8+记忆T细胞在OC微环境中表现出类似茎状的特性（茎）。目的2是测试我们的假设，即不同的表观遗传组蛋白轮廓与OC微环境中的特定CD8+记忆T细胞亚群有关。 AIM 3是测试我们的假设：EZH2/INK4A/ARF途径重要确定了CD8+记忆T细胞的命运，并重新编程了该途径可产生潜在的长期抗肿瘤免疫力。公共卫生相关性：我们对人类肿瘤微环境中记忆CD8+ T细胞的理解远远落后于对传染病模型中这些细胞的更全面分析。这种缺乏的温度显着，我们为理解基本的人类记忆T细胞生物学和潜在应用而努力。该应用通过结合基本免疫学方法，遗传和表观遗传学研究以及临床和比较分析来解决人类肿瘤微环境中记忆CD8+ T细胞的性质。该应用在概念上和适当的意义上是有效的，它将对癌症免疫疗法和疫苗接种的新方法产生新的见解。