Role of IRF2BP2 in Tumor Immune Evasion

IRF2BP2 在肿瘤免疫逃避中的作用

• 批准号: 10626010
• 负责人: muta abiff
• 金额: $ 5.27万
• 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/10626010
• 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 Promotion; Up-Regulation; Work; anti-tumor immune response; cancer infiltrating T cells; cell type; cofactor; cytokine; driver mutation; genetic corepressor; immune cell infiltrate; 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)和与其相关的细胞预后 对于开发髓母细胞瘤(MB)的新疗法至关重要，MB是儿童最常见的恶性脑肿瘤 肿瘤。MB(MM1)小鼠模型的免疫耐受与肿瘤表达增强有关 免疫检查点程序性死亡配体-1(PD-L1)对抗肿瘤细胞因子干扰素-γ的反应 (干扰素γ)信号。通过敲除细胞周期蛋白依赖性激酶5(CDK5)来阻断这一途径，CDK5是一种重要的 干扰素γ信号的转导，导致炎症的TME表型和体内增强的肿瘤排斥反应。 干扰素γ诱导的PD-L1基因表达被认为是在启动子水平上通过竞争 转录激活因子IRF1和抑制因子IRF2。干扰素γ-CDK5信号通路降低IRF2表达和IS 与其辅阻遏子IRF2BP2的低磷酸化相关，驱动IRF1介导的转录 激活。 IRF2BP2在多种细胞类型中已成为一种重要的转录辅助因子，在调节 细胞凋亡、细胞周期和炎症。然而，它在癌症中的作用还不是很清楚。我们假设 IRF2/IRF2BP2共抑制子的形成通常会减弱PD-L1的转录，而对这种转录的抑制 干扰素γ-CDK5信号复合体释放PD-L1表达，导致免疫逃避。这个项目的目的是 在基础和干扰素γ过程中，在PD-L1启动子水平上评估IRF2/IRF2BP2复合体的功能。 MB中的刺激条件，并补充研究这种肿瘤内在信号的扰动是如何 途径导致体内TME组成的变化。目标1将描述IRF2BP2在调节 含有干扰素敏感反应元件(ISRE)的基因启动子的功能。目标2将评估 IRF2BP2对肿瘤生长和免疫侵袭的影响这一努力的成功将使我们能够深入 了解肿瘤对MB免疫敏感性的内在调节，从而促进合理的靶向 未来针对MB和可能的其他癌症的免疫治疗方法的发展。