Regulation of Cross-Tolerance to Tumor Antigens

肿瘤抗原交叉耐受的调节

基本信息

批准号：
8610249
负责人：
EDUARDO M. SOTOMAYOR
金额：
$ 27.34万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
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：
2003-04-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610249
关键词：
Address Animal Model Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Antigens Attention Bone Marrow CD4 Positive T Lymphocytes Cells Chromatin Dendritic Cells Development Epigenetic Process Flagellin Funding Gene Expression Genes Genetic Goals Grant Histone Deacetylase Histone Deacetylation Histones Human Immune Immune Tolerance Immune system Immunity Inflammation Inflammatory Inflammatory Response Interleukin-10 Laboratories Ligands Ligation Malignant Neoplasms Mediating Molecular Mus Names Paralysed Pathway interactions Phosphorylation Play Proto-Oncogene Protein c-kit Regulation Reporter Role STAT3 gene Signal Pathway Signal Transduction T cell response T-Cell Activation T-Lymphocyte TLR5 gene Tail Testing Time Transgenic Mice Tumor Antigens base cancer cell cancer immunotherapy chromatin modification cytokine design histone deacetylase 6 in vivo insight neoplastic cell novel promoter public health relevance response tool tumor

项目摘要

DESCRIPTION (provided by applicant): Tumor-induced T-cell tolerance imposes a remarkable barrier to cancer immunotherapy. Bone marrow (BM) derived APCs play a central role in the induction of this state of unresponsiveness to tumor antigens. During the prior funding period of this grant, we have identified several signaling pathways that, by regulating the inflammatory status of the APC are critical in the decision leading to T-cell activation versus T-cell tolerance. More recently, we have focused our attention to mechanistically understand the regulation of inflammatory/anti-inflammatory genes in its natural setting, the chromatin substrate. In particular, we have studied the consequences of chromatin modification mediated by histone deacetylases upon the expression of genes involved in the inflammatory response. Our studies have unveiled for the first time that the histone deacetylase 11 (HDAC11) negatively regulates the expression of the anti-inflammatory cytokine IL-10 in murine and human APCs. Such an effect not only determines the inflammatory status of these cells but also influence priming versus tolerance of antigen-specific CD4+ T cells. In addition, we have found that histone deacetylase 6 (HDAC6) induce the opposite effect, i.e. enhanced IL-10 gene expression. These observations along with our recent finding that HDAC11 and HDAC6 interact with each other provide the framework to mechanistically address their role in regulating inflammatory responses in APCs and T-cells. The hypothesis to be tested is that dynamic changes at the chromatin level induced by HDAC6 and/or HDAC11 might influence the intrinsic plasticity of the APC to determine T-cell activation versus T-cell tolerance. The combination of experimental tools and animals models of T-cell tolerance we have developed during the past several years, together with the availability of mice with genetic disruption of HDAC11 or HDAC6 would allow us to determine whether these HDACs regulate inflammatory responses in murine and human APCs (Aim 1) and to assess their role in influencing CD4+ T-cell priming versus tolerance to tumor antigens in vivo (Aim 2). In addition, we propose studies to gain insights into the molecular mechanism(s) by which HDAC6 and HDAC11 regulate inflammation and the development of immunity versus tolerance (Aim 3). We believe that this comprehensive, mechanistically-oriented and translational project would unveil novel targets to overcome the barrier that tolerance to tumor antigens has imposed to the field of cancer immunotherapy.

描述（由申请人提供）：肿瘤诱导的 T 细胞耐受对癌症免疫治疗造成了显着的障碍。骨髓 (BM) 来源的 APC 在诱导这种对肿瘤抗原无反应的状态中发挥着核心作用。在本次资助的前期资助期间，我们已经确定了几种信号传导途径，通过调节 APC 的炎症状态，这些信号传导途径对于决定 T 细胞激活与 T 细胞耐受至关重要。最近，我们将注意力集中在从机制上理解炎症/抗炎基因在其自然环境（染色质底物）中的调节。特别是，我们研究了组蛋白脱乙酰酶介导的染色质修饰对参与炎症反应的基因表达的影响。我们的研究首次揭示了组蛋白脱乙酰酶 11 (HDAC11) 负向调节小鼠和人类 APC 中抗炎细胞因子 IL-10 的表达。这种效应不仅决定这些细胞的炎症状态，还影响抗原特异性 CD4+ T 细胞的启动与耐受。此外，我们发现组蛋白脱乙酰酶 6 (HDAC6) 会产生相反的作用，即增强 IL-10 基因的表达。这些观察结果以及我们最近发现的 HDAC11 和 HDAC6 相互作用，为从机制上解决它们在调节 APC 和 T 细胞炎症反应中的作用提供了框架。待测试的假设是，HDAC6 和/或 HDAC11 诱导的染色质水平的动态变化可能会影响 APC 的内在可塑性，从而确定 T 细胞激活与 T 细胞耐受性。结合我们在过去几年中开发的 T 细胞耐受性实验工具和动物模型，以及 HDAC11 或 HDAC6 基因破坏的小鼠的可用性，将使我们能够确定这些 HDAC 是否调节小鼠和人类的炎症反应。 APC（目标 1）并评估其在影响 CD4+ T 细胞启动与体内肿瘤抗原耐受性方面的作用（目标 2）。此外，我们提出研究来深入了解 HDAC6 和 HDAC11 调节炎症以及免疫与耐受的发展的分子机制（目标 3）。我们相信，这个全面的、以机制为导向的转化性项目将揭示新的靶点，以克服肿瘤抗原耐受给癌症免疫治疗领域带来的障碍。