Regulation of Cross-Tolerance to Tumor Antigens

肿瘤抗原交叉耐受的调节

• 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
• 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

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施加了显著的障碍。骨髓(BM)来源的APC在诱导这种对肿瘤抗原无反应的状态中起着核心作用。在这笔赠款的前一次资助期间，我们已经确定了几条信号通路，通过调节APC的炎症状态，这些通路在导致T细胞激活与T细胞耐受的决定中起着关键作用。最近，我们将注意力集中在从机制上理解发炎/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)负性调节抗炎细胞因子IL-10在小鼠和人APC中的表达。这种效应不仅决定了这些细胞的炎症状态，还影响了抗原特异性CD4+T细胞的启动和耐受。此外，我们还发现组蛋白脱乙酰基酶6(HDAC6)具有相反的作用，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，提供了一个框架，从机械上解决它们在调节APC和T细胞的炎症反应中的作用。需要检验的假设是，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，以确定T细胞的激活与T细胞的耐受。我们在过去几年中开发的T细胞耐受性的实验工具和动物模型，加上HDAC11或HDAC6基因突变的小鼠的可用性，将使我们能够确定这些HDACs是否调节小鼠和人类APC的炎症反应(目标1)，并评估它们在影响体内CD4+T细胞启动与对肿瘤抗原耐受性方面的作用(目标2)。此外，我们建议进行研究，以深入了解HDAC6和HDAC11调节炎症和免疫对抗耐受发展的分子机制(S)(目标3)。我们相信，这一综合性、机械性和转化性的项目将揭开新的靶点，以克服肿瘤抗原耐受性对癌症免疫治疗领域造成的障碍。