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
- 来源:
- 关键词:AffectAntigen PresentationAntigen Presentation PathwayAutomobile DrivingBiological AssayBiological ModelsBrain NeoplasmsCD8-Positive T-LymphocytesCell Differentiation processCell physiologyCellsCellular AssayCellular biologyChIP-seqChromatinClinicalCombined Modality TherapyDataDendritic CellsDetectionDiseaseEnzymesEpigenetic ProcessGene ExpressionGene Expression RegulationGlioblastomaGoalsHistone H3HistonesHumanImageImmuneImmune responseImmunosuppressionImmunotherapyIn VitroInfiltrationInflammatoryInterferonsKnowledgeLinkLysineMacrophageMediatingMicrogliaMissionModelingMusMyelogenousMyeloid CellsMyeloid-derived suppressor cellsOutcomePathway interactionsPatientsPeripheral Blood Mononuclear CellPhagocytesPhagocytosisPhagocytosis InhibitionPhenotypePlayPre-Clinical ModelPrognosisPublic HealthRNAResearchResistanceResolutionRoleSamplingSystemT cell infiltrationT cell regulationT-Cell ActivationT-LymphocyteTestingTherapeuticTransposaseTumor ImmunityUnited States National Institutes of HealthWorkanti-PD1 therapycheckpoint therapycombinatorialeffective therapyeffector T cellefficacy evaluationepigenetic regulationhistone demethylaseimmune resistanceimprovedindexinginflammatory milieuinnovationinsightmouse modelnovel strategiespersonalized immunotherapypharmacologicpre-clinicalprogramsresponseselective expressionsingle cell analysissingle-cell RNA sequencingsmall molecule inhibitorstandard of caretherapy resistanttreatment strategytumortumor microenvironmenttumor-immune system interactions
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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