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

项目摘要/摘要 巨噬细胞分化为活化的M1(炎症)和M2(免疫抑制)亚群是关键 免疫功能。未能适当地调节极化可能导致慢性炎症、自身免疫、 以及癌症的进展。在恶性肿瘤中，免疫抑制肿瘤相关巨噬细胞的极化 (TAMS)是许多实体肿瘤预后的有力预测指标，并且一直是 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 阻滞剂(ICB)和CAR-T细胞疗法。巨噬细胞极化受信号诱导状态的驱动 与SWI/SNF家族ATP依赖的染色质重塑复合体协同作用的转录因子 以改变DNA的可及性，并创造持续的基因表达变化。在初步研究中，我有 发现SWI/SNF活性是M2巨噬细胞极化的关键，我们认为这种依赖关系具有 有可能成为预防免疫抑制剂在实体瘤中蓄积的治疗靶点。我们 假设SWI/SNF家族染色质重构体(BAF/PBAF/GBAF)对获得 免疫抑制巨噬细胞表型及其在产生染色质可及性中的不同作用 在IL-4的极化过程中。我们希望这些重构体能够通过产生DNA来激活基因 极化诱导的STAT转铁蛋白结合位点在基因组中的可及性。为了解决这个中心问题 假设，我们将抑制SWI/SNF活性，然后确定IL-4诱导的M2对SWI/SNF的依赖 通过功能、转录和表观基因组图谱进行极化。我们还将验证SWI/SNF的作用 免疫活性小鼠癌症模型对肿瘤微环境的抑制作用。通过这件事 建议，我们的目标是利用SWI/SNF染色质重构体的贡献来控制的表型 癌症。了解调节M2极化的表观遗传特征将提供机会 通过减少TAMs的抗炎极化表型来改善患者的预后。因此，我们的 这项工作有可能帮助将免疫上的“冷”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.”