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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：
Sangeeta Goswami
金额：
$ 47万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
https://reporter.nih.gov/project-details/10634277
关键词：
Affect Antigen Presentation Antigen Presentation Pathway Automobile Driving Biological Assay Biological Models Brain Neoplasms CD8-Positive T-Lymphocytes Cell Differentiation process Cell physiology Cells Cellular Assay Cellular biology ChIP-seq Chromatin Clinical Combined Modality Therapy Data Dendritic Cells Detection Disease Enzymes Epigenetic Process Gene Expression Gene Expression Regulation Glioblastoma Goals Histone H3 Histones Human Image Immune Immune response Immunosuppression Immunotherapy In Vitro Infiltration Inflammatory Interferons Knowledge Link Lysine Macrophage Mediating Microglia Mission Modeling Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Outcome Pathway interactions Patients Peripheral Blood Mononuclear Cell Phagocytes Phagocytosis Phagocytosis Inhibition Phenotype Play Pre-Clinical Model Prognosis Public Health RNA Research Resistance Resolution Role Sampling System T cell infiltration T cell regulation T-Cell Activation T-Lymphocyte Testing Therapeutic Transposase Tumor Immunity United States National Institutes of Health Work anti-PD1 therapy checkpoint therapy combinatorial effective therapy effector T cell efficacy evaluation epigenetic regulation histone demethylase immune resistance improved indexing inflammatory milieu innovation insight mouse model novel strategies personalized immunotherapy pharmacologic pre-clinical programs response selective expression single cell analysis single-cell RNA sequencing small molecule inhibitor standard of care therapy resistant treatment strategy tumor tumor microenvironment tumor-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/摘要骨髓细胞介导的免疫抑制是导致抗病毒药物耐药的主要因素之一。程序性细胞死亡蛋白1（PD-1）疗法。胶质母细胞瘤（GBM），一种预后不良的脑肿瘤在目前的标准治疗中，肿瘤中富含免疫抑制性髓系细胞亚群，微环境中，并显示抗PD-1治疗的抗性。因此，有一个未得到满足的需要，克服骨髓源性免疫抑制的策略，以提供抗- GBM患者的PD-1治疗。表观遗传机制在髓样细胞分化中起关键作用，建立具体的职能概况。然而，肿瘤内髓系细胞的表观遗传调控的影响，细胞对免疫疗法的抗性仍然没有被探索。本提案的总体目标确定调节免疫抑制途径的关键表观遗传因子，并开发新的策略，靶向表观遗传调节因子以逆转GBM中的骨髓源性免疫抑制。在我们的初步研究中，我们注意到人类GBM肿瘤中的免疫抑制性髓系细胞亚群，表观遗传酶-组蛋白3赖氨酸27脱甲基酶（KDM 6 B）的高表达。GBM荷瘤小鼠携带骨髓细胞特异性Kdm 6 b缺失的人的存活率提高。此外，缺乏 Kdm 6 b增加染色质可及性和与促炎通路相关的基因表达包括肿瘤内巨噬细胞中的干扰素应答、吞噬能力和抗原呈递，树突状细胞重要的是，用GSK-J 4（一种小分子抑制剂）对KDM 6 B的药理学抑制，增强了抗PD-1治疗在GL 261荷瘤小鼠中的疗效，并增加了效应T细胞的浸润细胞基于初步发现，我们假设KDM 6 B抑制重新编程免疫- 抑制骨髓细胞转化为促炎表型，从而增强T细胞介导的抗肿瘤免疫力以克服GBM中抗PD-1疗法的抗性。在目前的提案中，我们将测试我们的假设使用三个具体的目的：1）确定KDM 6 B介导的功能和表观遗传的机制， 2）确定KDM 6 B在髓系细胞介导的免疫应答中的作用， T细胞功能和定位的调节;和3）评估KDM 6 B抑制在T细胞功能和定位中的治疗潜力。逆转对抗PD-1治疗的抗性。申请人认为这项研究是创新的，因为该提案将是第一个提供系统水平的理解表观遗传调控的作用，骨髓细胞生物学在GBM的单细胞分辨率。这项研究具有重要意义，因为它将研究靶向表观遗传机制以克服骨髓细胞源性免疫的新策略 GBM中抗PD-1治疗的耐药性。这项奋进的长期目标是开发以肿瘤特异性方式使用表观遗传调节剂的个性化免疫疗法。