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

项目概要/摘要 巨噬细胞极化为活化的M1（炎症）和M2（免疫抑制）亚群是关键， 免疫功能不能正确调节极化可导致慢性炎症、自身免疫， 和癌症进展。在恶性肿瘤中，免疫抑制性肿瘤相关巨噬细胞的极化 （TAMs）是许多实体瘤预后的强预测因子，并且一直是治疗的重大障碍。 免疫疗法旨在激活强大的抗癌T细胞反应，包括免疫检查点 阻断（ICB）和CAR-T细胞疗法。巨噬细胞极化由信号诱导的STAT驱动 与SWI/SNF家族ATP依赖性染色质重塑复合物协同作用的转录因子 来改变DNA的可及性并产生持续的基因表达变化。在初步研究中，我 发现SWI/SNF活性对M2巨噬细胞极化至关重要，我们相信这种依赖性具有 潜在的治疗靶向预防免疫抑制性TAM在实体瘤中的积累。我们 假设SWI/SNF家族染色质重塑（BAF/PBAF/GBAF）对获得 免疫抑制性巨噬细胞表型并在产生染色质可及性中发挥不同作用 在IL-4的极化过程中。我们认为这些重塑因子通过生成DNA 极化诱导的STAT TF结合位点在整个基因组中的可及性。为了解决这个中心问题， 假设，我们将抑制SWI/SNF活性，然后鉴定IL-4诱导的M2的SWI/SNF依赖性 通过功能、转录组学和表观基因组学分析进行极化。我们还将确认SWI/SNF的作用 在癌症的免疫活性小鼠模型中对肿瘤微环境的抑制。通过这个 我们的目标是利用SWI/SNF染色质重塑的贡献来控制TAM表型， 癌了解调节M2极化的表观遗传特征将为我们提供机会， 通过减少TAM的抗炎极化表型改善患者结局。结果我们的 这项工作有可能帮助将免疫学上“冷”的肿瘤“热”起来。

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.”