Role of IRF2BP2 in Tumor Immune Evasion

IRF2BP2 在肿瘤免疫逃避中的作用

• 批准号: 10231332
• 负责人: muta abiff
• 金额: $ 5.1万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10231332
• 关键词: Address; Antitumor Response; Apoptosis; Attenuated; Automobile Driving; CD4 Positive T Lymphocytes; Cell Cycle; Cells; Characteristics; Childhood Malignant Brain Tumor; Complex; Cyclin-Dependent Kinase 5; Data; Development; EphA5 Receptor; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Harvest; IRF1 gene; ITGAM gene; Immune; Immune Evasion; Immune response; Immunocompetent; Immunologic Markers; Immunotherapeutic agent; Immunotherapy; Inflammation; Inflammatory; Intention; Interferon Type II; Interferons; Intervention; Investigation; Knowledge; Maintenance; Malignant Neoplasms; Mediating; Modeling; Mus; Mutation; Myeloid Cells; Pathway interactions; Phenotype; Phosphotransferases; Play; Proteins; Regulation; Resistance; Response Elements; Role; SHH gene; Signal Pathway; Signal Transduction; Site; Subgroup; Testing; Transcription Coactivator; Transcriptional Activation; Transducers; Tumor Cell Line; Tumor Escape; Tumor Immunity; Tumor-infiltrating immune cells; Up-Regulation; Work; anti-tumor immune response; cell type; cytokine; driver mutation; genetic corepressor; immune checkpoint; immune checkpoint blockade; immune resistance; immunogenicity; immunoregulation; in vivo; knock-down; medulloblastoma; mouse model; neoantigens; neoplastic cell; neuropsychiatry; novel; novel therapeutics; prognostic; programmed cell death ligand 1; promoter; response; stem; success; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT ABSTRACT Understanding the tumor microenvironment (TME) and the prognostic relevance of the cells contributing to it is vital for developing novel treatments for medulloblastoma (MB), the most common malignant pediatric brain tumor. Immune resistance in a murine model of MB (MM1) is associated with enhanced tumor expression of the immune checkpoint programmed death ligand-1 (PD-L1) in response to anti-tumor cytokine interferon-gamma (IFNγ) signaling. Disruption of this pathway via knockdown of cyclin dependent kinase 5 (CDK5), an essential transducer of the IFNγ signal, leads to an inflammatory TME phenotype and enhanced tumor rejection in vivo. IFNγ-induced PD-L1 gene expression is thought to be regulated at the promoter level by competition between the transcriptional activator IRF1 and repressor IRF2. IFNγ-Cdk5 signaling decreases IRF2 expression and is associated with hypo-phosphorylation of its co-repressor IRF2BP2, driving IRF1-mediated transcriptional activation. IRF2BP2 has emerged as a vital transcriptional co-factor in multiple cell types, with roles in the regulation of apoptosis, cell cycling, and inflammation. However, its function in cancer is poorly defined. We hypothesize that formation of the IRF2/IRF2BP2 co-repressor normally attenuates PD-L1 transcription, and that inhibition of this complex by IFNγ-Cdk5 signaling unleashes PD-L1 expression and results in immune evasion. This project aims to assess the function of the IRF2/IRF2BP2 complex at the PD-L1 promoter level during basal and IFNγ- stimulated conditions in MB, with complementary studies on how perturbations in this tumor-intrinsic signaling pathway leads to shifts in the TME composition in vivo. Aim 1 will characterize the role of IRF2BP2 in mediating the function of interferon-sensitive response elements (ISRE)-containing gene promoters. Aim 2 will assess the effect of IRF2BP2 on tumor growth and immune infiltration in vivo. Success in this effort will enable an in-depth understanding of the tumor-intrinsic regulation of immune sensitivities in MB, thereby facilitating rational targeted immunotherapeutic approach development in the future against MB and possibly other cancers.

项目摘要 了解肿瘤微环境（TME）及其促成其细胞的预后相关性是 开发髓母细胞瘤（MB）的新型治疗方法，这是最常见的恶性小儿大脑 瘤。 MB的鼠模型中的免疫耐药性（MM1）与增强的肿瘤表达有关 免疫检查点编程的死亡配体1（PD-L1），以响应抗肿瘤细胞因子干扰素 - γ （IFNγ）信号传导。通过敲除细胞周期蛋白依赖激酶5（CDK5）的破坏，这是必不可少的 IFNγ信号的传感器会导致体内炎症性TME表型和增强的肿瘤排斥。 认为IFNγ诱导的PD-L1基因表达被认为是通过启动子水平调节的 转录激活器IRF1和复制器IRF2。 IFNγ-CDK5信号传导降低了IRF2的表达，IS 与其共抑制剂IRF2BP2的低磷酸化有关，驱动IRF1介导的转录 激活。 IRF2BP2已成为多种细胞类型中的重要转录共同因素，在调节中的作用 凋亡，细胞循环和炎症。但是，其在癌症中的功能很差。我们假设这一点 IRF2/IRF2BP2共抑制剂的形成通常会削弱PD-L1转录，并抑制它 IFNγ-CDK5信号传导的复合物释放了PD-L1的表达，并导致免疫抗性。这个项目的目标 评估在碱性和IFNγ-的PD-L1启动子水平上IRF2/IRF2BP2复合物的功能 MB的刺激条件，对这种肿瘤内部信号的扰动如何进行完整的研究 途径导致体内TME组成的变化。 AIM 1将表征IRF2BP2在中介中的作用 含有干扰素敏感响应元件（ISRE）含有基因启动子的功能。 AIM 2将评估 IRF2BP2对体内肿瘤生长和免疫浸润的影响。这项努力的成功将使您能够深入 了解MB免疫敏感性的肿瘤内部调节，从而支持有理性的目标 未来针对MB和其他可能的癌症的免疫治疗方法开发。