Function and Mechanism of TET Regulation of Tumor Immunity

TET调节肿瘤免疫的功能及机制

• 批准号: 10020932
• 负责人: ALBERT Sidney BALDWIN
• 金额: $ 31.94万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020932
• 关键词: Affect; Binding; Chromatin; Chronic; Cytokine Signaling; DNA; DNA Modification Process; Development; Dioxygenases; Enzymes; Epigenetic Process; Family; Foundations; Fumarates; Funding; Gene Activation; Gene Expression; Genes; HIV; Hematopoietic Neoplasms; Histone Deacetylase; Human; Hypermethylation; Immunotherapy; Impairment; Inflammation; Inflammatory; Interferons; Interleukin-6; Intrahepatic Cholangiocarcinoma; Investigation; Isocitrate Dehydrogenase; Liver; Lymphomagenesis; Malignant Neoplasms; Mediating; Metabolic; Methylation; Mouse Strains; Mus; Mutation; NFKB Signaling Pathway; Pathogenesis; Pathway interactions; Play; Primary Neoplasm; Production; Proteins; Recurrent tumor; Regulation; Resistance; Resolution; Role; Series; Signal Pathway; Signal Transduction; Solid Neoplasm; Structure; Succinates; Suggestion; Technology; Testing; Therapeutic; Tumor Immunity; Tumor Suppression; Tumor-Derived; Tumor-infiltrating immune cells; WT1 gene; alpha ketoglutarate; base; cancer genomics; chemokine; cytokine; demethylation; design; gene discovery; gene repression; genetic analysis; histone demethylase; histone modification; improved; in vivo; loss of function mutation; member; mutant; neoplasm immunotherapy; novel; promoter; recruit; response; transcription factor; tumor; ubiquitin-protein ligase; vpr Gene Products

Project Abstract Nearly half of newly discovered cancer driver genes discovered by the cancer genomic studies encode proteins involved in histone or DNA modification, including the TET family of DNA dioxygenases. Loss-of-function mutations in TET genes occur early and frequently in human hematopoietic malignancy. Mutations in TET genes, however, are uncommon in solid tumors. Instead, TET activity is significantly reduced in different types of human tumors. We do not know the significance of decreased TET activity in solid tumors. In this study, we hypothesize that TET has a previously unrecognized key function in both the JAK-STAT and NF-κ pathways. Inactivation of TET in results in chronic tumor-promoting inflammation and escape from anti-tumor immunity. Thus, stimulating TET activity represents a viable opportunity to enhance antitumor immunity and to improve immunotherapy. We will test this hypothesis by defining the following aspects of TET2 activity: The function and mechanism of TET2 in the JAK-STAT pathway and in tumor immunity (Aim 1); The regulation of TET2 and tumor immunity by reversible monoubiquitylation (Aim 2); and The catalytically independent function and mechanism of TET2 in tumor suppression (Aim 3). During the past funding period, we have made the following discoveries that significantly affect the TET field and that form the foundation for this investigation: (1) Multiple oncometabolites produced or accumulated by mutations in different metabolic enzymes act as antagonists α-ketoglutarate (αKG) and inhibit multiple αKG- dependent enzymes, including TET enzymes. (2) TET activity is dynamically regulated in vivo. (3) Development of solid tumors of many different types is associated with a substantial decrease in TET activity. (4) TET is reversibly monoubiquitylated by CRL4VprBP E3 ligase and UPS15 deubiquitylase, enhancing and impairing TET activity, respectively. This regulation is disrupted by multiple recurrent tumor-derived mutations in TET2. (5) HIV protein Vpr reprograms CRL4VprBP E3 ligase to catalyze polyubiquitylation and degradation of TET proteins to sustain the expression of pro-inflammatory cytokine and promote HIV pathogenesis. (6) Multiple sequence- specific transcription factors (TFs) recruit TET2 to their target genes, including members of NF-κB and STAT families. (7) Loss of TET2 function in tumors impairs interferon signaling, chemokine production, and T cell infiltration, and confers resistance to tumor immunity and immunotherapy. This investigation is built on our pioneering and extensive study of the then newly discovered TET enzymes. It will investigate a novel aspect of cytokine signaling and tumor immunity regulation—by TET- mediated DNA demethylation. It will use newly developed technology and mouse strains to determine how TET proteins regulate gene expression by catalytically-dependent and -independent mechanisms. It will explore a novel regulation of TET by reversible monoubiquitylation and the therapeutic opportunity of this regulation. This investigation represents the first exploration on the function and mechanism of TET in tumor immunity.

项目摘要 通过癌症基因组研究发现的新发现的癌症驱动基因中，将近一半编码蛋白质 参与组蛋白或DNA修饰，包括DNA二加氧酶的TET家族。功能丧失 TET基因的突变发生早期，并且经常发生在人类造血恶性肿瘤中。 TET基因的突变， 但是，在实体瘤中并不常见。相反，在不同类型的人类中，TET活性大大降低 肿瘤。我们不知道降低TET活性在实体瘤中的意义。在这项研究中，我们假设 该TET在JAK-STAT和NF-κ途径中具有先前未识别的关键功能。失活 TET导致慢性肿瘤注射并摆脱抗肿瘤免疫力。那是刺激的 TET活性代表了增强抗肿瘤免疫疗法并改善免疫疗法的可行机会。我们 将通过定义TET2活动的以下方面来检验该假设： JAK-Stat途径和肿瘤免疫中的TET2（AIM 1）； TET2和肿瘤的调节 可逆的单位素化的免疫力（AIM 2）；以及催化独立的功能和 肿瘤抑制中TET2的机理（AIM 3）。 在过去的资金期间，我们进行了以下发现，显着影响TET 田地和该投资的基础是：（1）由多个由副代谢产生或累积的 不同代谢酶的突变充当拮抗剂α-酮戊二酸（αkg），并抑制多个αkg- 依赖性酶，包括TET酶。 （2）TET活性在体内动态调节。 （3）发展 许多不同类型的实体瘤与TET活性大幅降低有关。 （4）Tet是 由CRL4VPRBP E3连接酶和UPS15去泛素酶可逆地倾斜的单位液化，增强和损害TET 分别活动。 TET2中的多个复发性肿瘤衍生的突变被残疾。 （5）艾滋病毒 蛋白质VPR重新编程CRL4VPRBP E3连接酶催化TET蛋白的多泛素化和降解为 维持促炎性细胞因子的表达并促进HIV发病机理。 （6）多个序列 - 特定的转录因子（TFS）将TET2募集到其靶基因，包括NF-κB和STAT的成员 家庭。 （7）肿瘤中TET2功能的丧失会损害干扰信号，趋化因子产生和T细胞 浸润，并赋予对肿瘤免疫疗法的抵抗。 这项投资建立在我们对当时新发现的TET的开创性和广泛的研究基础上 酶。它将研究细胞因子信号传导和肿瘤免疫学调节的新方面 - 介导的DNA脱甲基化。它将使用新开发的技术和鼠标应变来确定如何TET 蛋白质通过催化依赖性和非依赖性机制来调节基因表达。它将探索 通过可逆的单位素化和该调节的治疗机会对TET进行新的调节。这 研究是对TET在肿瘤免疫中的功能和机制的首次探索。