Regulation of IL-4 macrophage polarization by SWI/SNF family complexes

SWI/SNF 家族复合物对 IL-4 巨噬细胞极化的调节

• 批准号: 10464334
• 负责人: COURTNEY CHAMBERS
• 金额: $ 4.04万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2023-05-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464334
• 关键词: Address; Anti-Inflammatory Agents; Autoimmunity; Binding; Binding Sites; Biological Assay; CAR T cell therapy; Cancer Model; Cells; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Chronic; Co-Immunoprecipitations; DNA; Data; Dependence; Disease; Effector Cell; Epigenetic Process; Equilibrium; Failure; Family; Gene Activation; Gene Expression; Gene Targeting; Genes; Genome; Genomics; Glioblastoma; Head and Neck Cancer; Homeostasis; Immune; Immune response; Immune system; Immunocompetent; Immunologics; Immunotherapy; Infiltration; Inflammation; Inflammatory; Interleukin-4; Kinetics; Lead; Lymphoma; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Myelogenous; Myeloid-derived suppressor cells; Pathogenicity; Patient-Focused Outcomes; Phenotype; Play; Prognosis; Refractory; Regulation; Resistance; Resolution; Role; SMARCA4 gene; STAT6 gene; SWI/SNF Family Complex; Signal Transduction; Site; Solid Neoplasm; Stimulus; T cell response; T-Lymphocyte; Testing; Therapeutic; Tumor-associated macrophages; Tumor-infiltrating immune cells; Work; anti-cancer; cancer therapy; cancer type; chromatin remodeling; design; epigenomics; immune checkpoint blockade; immune function; immunoregulation; immunosuppressive macrophages; improved; in vivo; macrophage; malignant breast neoplasm; melanoma; mouse model; neoplasm immunotherapy; novel therapeutics; prevent; response; therapeutic target; tissue repair; tool; transcription factor; transcriptomics; tumor; tumor microenvironment; tumor progression

Project Summary/Abstract Macrophage polarization into activated M1 (inflammatory) and M2 (immunosuppressive) subsets is critical to immune function. The failure to properly regulate polarization can lead to chronic inflammation, autoimmunity, and cancer progression. In malignancy, the polarization of immunosuppressive tumor-associated macrophages (TAMs) is a strong predictor of prognosis for many solid tumors and has been a significant hurdle to immunotherapies designed to activate strong anti-cancer T cell responses, including immune checkpoint blockade (ICB) and CAR-T cell therapies. Macrophage polarization is driven by signal-induced STAT transcription factors, which cooperate with SWI/SNF-family ATP-dependent chromatin remodeling complexes to alter DNA accessibility and to create sustained gene expression changes. In preliminary studies, I have found that SWI/SNF activity is critical to M2 macrophage polarization, and we believe this dependency has the potential to be therapeutically targeted to prevent immunosuppressive TAM accumulation in solid tumors. We hypothesize that SWI/SNF-family chromatin remodelers (BAF/PBAF/GBAF) are critical to the acquisition of immunosuppressive macrophage phenotypes and play differential roles in generating chromatin accessibility during polarization by IL-4. We expect that these remodelers enable gene activation by generating DNA accessibility across the genome for polarization-induced STAT TF binding sites. To address this central hypothesis, we will inhibit SWI/SNF activity, then identify the SWI/SNF dependencies of IL-4 induced M2 polarization via functional, transcriptomic, and epigenomic profiling. We will also validate the role of SWI/SNF inhibition on the tumor microenvironment in an immunocompetent mouse model of cancer. Through this proposal, we aim to leverage the contribution of SWI/SNF chromatin remodelers to control TAM phenotypes in cancer. Understanding the epigenetic features that regulate M2 polarization will provide opportunities to improve patient outcomes by reducing the anti-inflammatory polarization phenotypes of TAMs. As a result, our work has the potential to help turn immunologically “cold” tumors “hot.”

项目摘要/摘要 巨噬细胞极化为活化的M1（炎症）和M2（免疫抑制）亚集对 免疫功能。无法正确调节极化会导致慢性感染，自身免疫性， 和癌症的进展。在恶性肿瘤中，免疫抑制肿瘤相关的巨噬细胞极化 （TAM）是许多实体瘤的预后预测指标，并且是一个重大障碍 旨在激活强抗癌T细胞反应的免疫疗法，包括免疫切除点 胃（ICB）和CAR-T细胞疗法。巨噬细胞极化是由信号诱导的STAT驱动的 转录因子，与SWI/SNF家庭ATP依赖性染色质重塑配合物协调 改变DNA可及性并创造持续的基因表达变化。在初步研究中，我有 发现SWI/SNF活动对于M2巨噬细胞极化至关重要，我们认为这种依赖性具有 可能被热靶向以防止在实体瘤中的免疫抑制TAM积累。我们 假设SWI/SNF家庭染色质重塑（BAF/PBAF/GBAF）对于获取至关重要 免疫抑制巨噬细胞表型，并在产生染色质的可及性方面发挥了不同的作用 在IL-4极化期间。我们期望这些远程通过产生DNA来激活基因 跨基因组的可访问性，用于极化引起的Stat TF结合位点。解决这个中央 假设，我们将抑制SWI/SNF活性，然后确定IL-4诱导M2的SWI/SNF依赖性 通过功能，转录组和表观基因组分析的极化。我们还将验证SWI/SNF的作用 抑制癌症的免疫能力小鼠模型中的肿瘤微环境。通过这个 提案，我们旨在利用SWI/SNF染色质改造的贡献，以控制TAM表型 癌症。了解调节M2极化的表观遗传特征将为 通过减少TAM的抗炎极化表型来改善患者预后。结果，我们的 工作有可能帮助将免疫学上的“冷”肿瘤变成“热”。