ATRX mutations, innate immune activation and therapeutic vulnerability in malignant gliomas

ATRX 突变、先天免疫激活和恶性胶质瘤的治疗脆弱性

• 批准号: 10375084
• 负责人: David M. Ashley
• 金额: $ 42.23万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375084
• 关键词: 19q; ATRX gene; Adaptive Immune System; Affect; Aftercare; Agonist; Astrocytoma; Brain; Cartoons; Cell Line; Cells; Chemosensitization; Chromosomes; Data; Dependence; Double-Stranded RNA; Gene Expression; Glioma; Goals; Human; Immune; Immune Response Genes; Immune checkpoint inhibitor; Immune signaling; Immune system; Immunobiology; Immunologic Surveillance; Immunologics; Immunotherapeutic agent; Immunotherapy; Infiltration; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Interferon Type I; Knock-out; Knockout Mice; Link; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Measures; Mediating; Mental Retardation; Modeling; Molecular Profiling; Mus; Mutate; Mutation; Natural Immunity; Oligodendroglioma-Astrocytoma; Operative Surgical Procedures; Patients; Poly ICLC; Primary Brain Neoplasms; Production; Proteins; RNA; Radiation; Relapse; Role; SWI/SNF Family Complex; Signal Transduction; Specimen; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tissues; Tumor Escape; Tumor Immunity; Work; alpha-Thalassemia; base; chemotherapy; chromatin remodeling; cohort; cytokine; effective therapy; immune activation; in vivo; inhibitor; innovation; insight; link protein; member; mutant; neoplastic cell; novel; oligodendroglioma; pre-clinical; resistance mechanism; response; therapeutic evaluation; therapy design; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

ABSTRACT Gliomas, including oligodendroglioma and astrocytoma subtypes, are a diverse group of malignant primary brain tumors that respond to radiation, surgery and chemotherapy; however, relapse remains a major barrier affecting overall patient survival. Immunotherapy targeting the adaptive immune system such as checkpoint inhibitors has shown limited efficacy in gliomas. Thus, understanding the immunobiology of gliomas and mechanisms of resistance to immune therapies is crucial to therapeutically leverage the immune system for treating patients. Our long-term goal is to dissect the innate immune system in gliomas and identify vulnerabilities that can be exploited for designing therapies. Recent studies have implicated a link between mutations in ATRX, a SWI-SNF chromatin remodeler and immune cell infiltration in the tumor microenvironment of ATRX-mutant astrocytomas. Our preliminary data suggest that ATRX inactivation in gliomas leads to enriched inflammatory signatures and potentiation of type I interferon/pro-inflammatory signaling, and selective sensitization of tumors to double-stranded (dsRNA)-based immune agonists. Based on these preliminary findings, we hypothesize that ATRX inactivation induces innate inflammation and sensitizes tumors to immune surveillance and dsRNA agonist therapy; concurrent IDH mutations suppress innate inflammation to enable tumor immune evasion. We will test our hypothesis in the following specific aims. Aim 1: Define the role of ATRX inactivation in modulating glioma cell-intrinsic innate signaling; Aim 2: Elucidate the role of ATRX deficiency and concurrent IDH1R132H mutation in modulating anti- tumor immunity and the response to dsRNA agonist therapy in pre-clinical murine glioma models; Aim 3: Determine the extent to which dsRNA-based therapies induce inflammatory activation of lower-grade gliomas. Our proposal will: 1) delineate the novel role of ATRX loss in regulating innate immune signaling responses and their downstream effects in glioma, 2) examine the immunological interplay between ATRX mutations and its partner mutation, IDH1R132H and 3) lay preclinical groundwork for exploiting a potential therapeutic vulnerability in gliomas carrying ATRX mutations.

抽象的 神经胶质瘤，包括少突神经胶质瘤和星形细胞瘤亚型，是一组不同的恶性原发性肿瘤 对放射、手术和化疗有反应的脑肿瘤；然而，复发仍然是一个主要障碍 影响患者的总体生存率。针对适应性免疫系统（例如检查点）的免疫疗法 抑制剂对神经胶质瘤的疗效有限。因此，了解神经胶质瘤的免疫生物学和 免疫疗法的抵抗机制对于治疗性利用免疫系统至关重要 治疗病人。我们的长期目标是剖析神经胶质瘤的先天免疫系统并找出漏洞 可用于设计疗法。 最近的研究表明 ATRX（一种 SWI-SNF 染色质重塑因子）的突变与 ATRX 突变型星形细胞瘤肿瘤微环境中的免疫细胞浸润。我们的初步数据 表明神经胶质瘤中 ATRX 失活导致炎症特征丰富和 I 型增强 干扰素/促炎信号传导以及肿瘤对基于双链 (dsRNA) 的选择性敏化 免疫激动剂。基于这些初步发现，我们假设 ATRX 失活会诱导先天性 炎症并使肿瘤对免疫监视和 dsRNA 激动剂治疗敏感；并发IDH 突变抑制先天炎症，使肿瘤免疫逃避。我们将检验我们的假设 遵循特定目标。目标 1：定义 ATRX 失活在调节神经胶质瘤细胞内在先天性中的作用 信号发送；目标 2：阐明 ATRX 缺陷和并发 IDH1R132H 突变在调节抗- 临床前小鼠神经胶质瘤模型中的肿瘤免疫和对 dsRNA 激动剂治疗的反应；目标 3： 确定基于 dsRNA 的疗法诱导低级别神经胶质瘤炎症激活的程度。 我们的提案将：1）描述 ATRX 丢失在调节先天免疫信号反应中的新作用 及其在神经胶质瘤中的下游效应，2) 检查 ATRX 突变和 其伴侣突变 IDH1R132H 和 3) 为利用潜在的治疗漏洞奠定了临床前基础 存在于携带 ATRX 突变的神经胶质瘤中。