Regulation of IL-4 macrophage polarization by SWI/SNF family complexes
Regulation of IL-4 macrophage polarization by SWI/SNF family complexes
批准号:
10464334
负责人:
COURTNEY CHAMBERS
金额:
$4.04万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-08-17 至 2023-05-24
关键词:
AddressAnti-Inflammatory AgentsAutoimmunityBindingBinding SitesBiological AssayCAR T cell therapyCancer ModelCellsChIP-seqChromatinChromatin Remodeling FactorChronicCo-ImmunoprecipitationsDNADataDependenceDiseaseEffector CellEpigenetic ProcessEquilibriumFailureFamilyGene ActivationGene ExpressionGene TargetingGenesGenomeGenomicsGlioblastomaHead and Neck CancerHomeostasisImmuneImmune responseImmune systemImmunocompetentImmunologicsImmunotherapyInfiltrationInflammationInflammatoryInterleukin-4KineticsLeadLymphomaMaintenanceMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMyelogenousMyeloid-derived suppressor cellsPathogenicityPatient-Focused OutcomesPhenotypePlayPrognosisRefractoryRegulationResistanceResolutionRoleSMARCA4 geneSTAT6 geneSWI/SNF Family ComplexSignal TransductionSiteSolid NeoplasmStimulusT cell responseT-LymphocyteTestingTherapeuticTumor-associated macrophagesTumor-infiltrating immune cellsWorkanti-cancercancer therapycancer typechromatin remodelingdesignepigenomicsimmune checkpoint blockadeimmune functionimmunoregulationimmunosuppressive macrophagesimprovedin vivomacrophagemalignant breast neoplasmmelanomamouse modelneoplasm immunotherapynovel therapeuticspreventresponsetherapeutic targettissue repairtooltranscription factortranscriptomicstumortumor microenvironmenttumor progression
中文摘要
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。
英文摘要
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.”
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