Role of IRF2BP2 in Tumor Immune Evasion

项目摘要 了解肿瘤微环境（TME）和促成肿瘤微环境的细胞的预后相关性， 对于开发髓母细胞瘤（MB）的新疗法至关重要，MB是最常见的儿童恶性脑肿瘤 肿瘤MB（MM 1）小鼠模型中的免疫耐药性与增强的肿瘤表达相关， 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应答 (IFNγ）信号传导。通过敲低细胞周期蛋白依赖性激酶5（CDK 5）来破坏该途径， IFNγ信号的转导子，导致炎性TME表型和体内增强的肿瘤排斥。 IFNγ诱导的PD-L1基因表达被认为是在启动子水平上通过与PD-L1基因之间的竞争来调节的。 转录激活因子IRF 1和阻遏因子IRF 2。IFNγ-Cdk 5信号转导降低IRF 2表达， 与其辅阻遏物IRF 2BP 2的低磷酸化相关，驱动IRF 1介导的转录 activation. IRF 2BP 2已成为多种细胞类型中重要的转录辅因子，在调节细胞增殖中起作用。 细胞凋亡、细胞周期和炎症。然而，其在癌症中的功能定义不清。我们假设 IRF 2/IRF 2BP 2共阻遏物的形成通常会减弱PD-L1转录，而这种抑制作用 通过IFNγ-Cdk 5信号传导的复合物释放PD-L1表达并导致免疫逃避。该项目旨在 评估IRF 2/IRF 2BP 2复合物在PD-L1启动子水平的功能， MB中的刺激条件，以及对这种肿瘤内在信号传导中的扰动如何进行补充研究 TME通路导致体内TME组成的变化。目的1将表征IRF 2BP 2在介导 含干扰素敏感反应元件（ISRE）基因启动子的功能。目标2将评估 IRF 2BP 2对体内肿瘤生长和免疫浸润的影响。这一努力的成功将使人们能够深入了解 了解MB中免疫敏感性的肿瘤内在调节，从而促进合理靶向 免疫途径的发展，在未来对MB和可能的其他癌症。

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.