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.

项目概要/摘要髓样细胞介导的免疫抑制是导致抗-抗-抗药性的主要因素之一。程序性细胞死亡蛋白 1 (PD-1) 治疗胶质母细胞瘤 (GBM)，一种预后不佳的脑肿瘤。采用当前标准护理疗法，其肿瘤中富含免疫抑制性骨髓细胞亚群微环境并对抗 PD-1 疗法表现出耐药性，因此，开发的需求尚未得到满足。克服髓源性免疫抑制的策略，以提供抗骨髓来源的持久临床益处 PD-1 治疗 GBM 患者的表观遗传机制在骨髓细胞分化和分化过程中发挥着关键作用。然而，肿瘤内骨髓的表观遗传调控的影响。细胞对免疫治疗的耐药性尚未得到探索目前提案的总体目标。是确定调节免疫抑制途径的关键表观遗传因素并制定新策略靶向表观遗传调节因子以逆转 GBM 中骨髓源性免疫抑制。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骨髓细胞亚群具有表观遗传酶 - 组蛋白 3 赖氨酸 27 去甲基化酶 (KDM6B) 高表达 GBM 肿瘤小鼠。此外，携带骨髓细胞特异性 Kdm6b 缺失的患者存活率也有所提高。 Kdm6b 增加染色质可及性和促炎途径相关基因的表达包括干扰素反应、吞噬能力和瘤内巨噬细胞的抗原呈递重要的是，小分子抑制剂 GSK-J4 对 KDM6B 的药理抑制作用，通过增加效应 T 浸润，增强 GL261 荷瘤小鼠抗 PD-1 治疗的疗效根据初步发现，我们发现 KDM6B 抑制会重新编程免疫细胞。抑制性骨髓细胞转化为促炎表型，从而增强 T 细胞介导的抗肿瘤作用免疫来克服 GBM 中抗 PD-1 治疗的耐药性在当前的提案中，我们将检验我们的假设。使用三个具体目标：1) 确定 KDM6B 介导的功能和表观遗传机制吞噬作用和抗原呈递的调节；2) 确定 KDM6B 在骨髓细胞介导中的作用 T 细胞功能和定位的调节；3) 评估 KDM6B 抑制的治疗潜力申请人认为该研究具有创新性，因为它逆转了抗 PD-1 疗法的耐药性。该提案将是第一个提供对表观遗传调控作用的系统级理解的提案之一 GBM 中单细胞分辨率的骨髓细胞生物学这项研究具有重要意义，因为它将研究一种针对表观遗传机制来克服骨髓细胞衍生免疫系统的新策略 GBM 中抗 PD-1 疗法的耐药性这项研究的长期目标是开发。以肿瘤特异性方式使用表观遗传调节剂进行个性化免疫治疗。