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

项目概要/摘要 巨噬细胞极化为激活的 M1（炎症）和 M2（免疫抑制）亚群对于 免疫功能。未能正确调节极化可能导致慢性炎症、自身免疫、 和癌症进展。在恶性肿瘤中，免疫抑制肿瘤相关巨噬细胞的极化 （TAM）是许多实体瘤预后的强有力预测因素，并且一直是治疗的一个重大障碍。 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 转录因子，与 SWI/SNF 家族 ATP 依赖性染色质重塑复合物配合 改变 DNA 可及性并产生持续的基因表达变化。在初步研究中，我有 发现 SWI/SNF 活性对于 M2 巨噬细胞极化至关重要，我们认为这种依赖性具有 有可能成为治疗靶点，以防止实体瘤中免疫抑制 TAM 的积累。我们 假设 SWI/SNF 家族染色质重塑因子 (BAF/PBAF/GBAF) 对于获得 免疫抑制巨噬细胞表型并在产生染色质可及性方面发挥不同作用 在 IL-4 极化期间。我们期望这些重塑剂能够通过生成 DNA 来激活基因 极化诱导的 STAT TF 结合位点在整个基因组中的可及性。为了解决这个中央 假设，我们将抑制 SWI/SNF 活性，然后确定 IL-4 诱导的 M2 的 SWI/SNF 依赖性 通过功能、转录组和表观基因组分析进行极化。我们还将验证 SWI/SNF 的作用 对免疫活性小鼠癌症模型中肿瘤微环境的抑制。通过这个 提案中，我们的目标是利用 SWI/SNF 染色质重塑剂的贡献来控制 TAM 表型 癌症。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 的抗炎极化表型来改善患者的预后。结果，我们的 这项工作有可能帮助免疫学上的“冷”肿瘤变得“热”。

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.”