Targeting epigenetic machinery to overcome myeloid cell-mediated resistance to anti-PD-1 therapy in GBM

靶向表观遗传机制克服 GBM 中骨髓细胞介导的抗 PD-1 治疗耐药性

基本信息

  • 批准号:
    10634277
  • 负责人:
  • 金额:
    $ 47万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-01 至 2028-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Myeloid cell-mediated immune suppression is one of the major factors responsible for resistance to anti- programmed cell death protein 1 (PD-1) therapy. Glioblastoma (GBM), a brain tumor with a dismal prognosis with current standard-of-care therapy, is enriched with immune-suppressive myeloid cell subsets in its tumor microenvironment and shows resistance to anti-PD-1 therapy. Therefore, there is an unmet need to develop strategies to overcome myeloid-derived immune suppression in order to provide durable clinical benefits of anti- PD-1 therapy in patients with GBM. Epigenetic machinery plays a key role in myeloid cell differentiation and establishing specific functional profiles. However, the impact of epigenetic regulation of intra-tumoral myeloid cells on resistance to immunotherapy has remained unexplored. The overall objective of the current proposal is to identify key epigenetic factors regulating immune-suppressive pathways and develop a novel strategy targeting the epigenetic regulator(s) to reverse myeloid-derived immune suppression in GBM. In our preliminary studies, we noted that immune-suppressive myeloid cell subsets in human GBM tumors have high expression of an epigenetic enzyme - histone 3 lysine 27 demethylase (KDM6B). GBM tumor-bearing mice carrying myeloid-cell specific Kdm6b deletion demonstrated improved survival. Additionally, the absence of Kdm6b increased chromatin accessibility and expression of genes associated with proinflammatory pathways including interferon response, phagocytic ability, and antigen-presentation in intratumoral macrophages and dendritic cells. Importantly, pharmacological inhibition of KDM6B with GSK-J4, a small molecule inhibitor, enhanced the efficacy of anti-PD-1 therapy in GL261 tumor-bearing mice with increased infiltration of effector T cells. Based on the preliminary findings, we hypothesize that KDM6B inhibition reprograms immune- suppressive myeloid cells into a proinflammatory phenotype, thereby enhancing T cell-mediated anti-tumor immunity to overcome resistance to anti-PD-1 therapy in GBM. In the current proposal, we will test our hypothesis using three specific aims: 1) To determine the mechanism of KDM6B-mediated functional and epigenetic regulation of phagocytosis and antigen presentation; 2) To identify the role of KDM6B in myeloid cell-mediated regulation of T cell function and localization; and 3) To evaluate the therapeutic potential of KDM6B inhibition in reversing the resistance to anti-PD-1 therapy. The research is innovative in the applicant’s opinion because this proposal will be one of the first to provide systems-level understanding of the role of epigenetic regulation of myeloid cell biology at a single-cell resolution in GBM. The proposed research is significant since it will investigate a novel strategy of targeting the epigenetic machinery to overcome myeloid cell-derived immune resistance to anti-PD-1 therapy in GBM. The long-term goal of this research endeavor is to develop personalized immunotherapies with epigenetic modulators in a tumor-specific manner.
项目摘要/摘要 髓样细胞介导的免疫抑制是负责抗性抗性的主要因素之一 程序性细胞死亡蛋白1(PD-1)疗法。胶质母细胞瘤(GBM),一种脑肿瘤,预后较差 使用当前的护理标准疗法,在其肿瘤中用免疫抑制的髓样细胞亚群富集 微环境并显示出对抗PD-1治疗的抗性。因此,有未满足的需求 克服髓样衍生的免疫抑制的策略,以便提供抗抗临床益处 GBM患者的PD-1治疗。表观遗传机械在髓样细胞分化和 建立特定的功能曲线。但是,肿瘤内髓样的表观遗传调节的影响 对免疫疗法的抗性细胞仍然出乎意料。当前建议的总体目标 是确定调查免疫抑制途径的关键表观遗传因素并制定新的策略 靶向表观遗传调节剂,以逆转GBM中髓样衍生的免疫抑制。 在我们的初步研究中,我们注意到人GBM肿瘤中的免疫抑制髓样细胞亚群具有 表观遗传酶的高表达 - 组蛋白3赖氨酸27脱甲基酶(KDM6B)。 GBM肿瘤小鼠 携带髓样细胞特异性KDM6B缺失表现出改善的存活率。另外,没有 KDM6B增加了与促炎途径相关的基因的染色质访问性和表达 包括干扰素反应,吞噬能力和肿瘤内巨噬细胞中的抗原呈递 树突状细胞。重要的是,用小分子抑制剂GSK-J4对KDM6B的药物抑制作用, 增强了抗PD-1治疗在GL261肿瘤小鼠中的效率,并增加了效应的浸润 细胞。根据初步发现,我们假设KDM6B抑制作用重新编程 抑制髓样细胞成促炎的表型,从而增强了T细胞介导的抗肿瘤 克服GBM中抗PD-1治疗的抗性的免疫力。在当前的建议中,我们将检验我们的假设 使用三个特定目的:1)确定KDM6B介导的功能和表观遗传学的机制 调节吞噬作用和抗原表现; 2)确定KDM6B在髓样细胞介导的 调节T细胞功能和定位; 3)评估KDM6B抑制的治疗潜力 逆转抗PD-1治疗的抗性。申请人认为这项研究具有创新性,因为这 提案将是第一个提供系统级别理解表观遗传调节作用的提案之一 GBM中单细胞分辨率的髓样细胞生物学。拟议的研究很重要,因为它将 研究针对表观遗传机制以克服髓样细胞衍生的免疫的新型策略 GBM中抗PD-1治疗的抗性。这项研究的长期目标是发展 具有表观遗传调节剂的个性化免疫疗法以肿瘤特异性方式。

项目成果

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