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