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: 10666347
• 负责人: David M. Ashley
• 金额: $ 37.7万
• 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/10666347
• 关键词: 19q; Adaptive Immune System; Affect; Aftercare; Agonist; Astrocytoma; Cartoons; Cell Line; Cells; Chemosensitization; Chromatin; Chromosomes; Data; Dependence; Double-Stranded RNA; Gene Expression; Gene Proteins; Glioma; Goals; Human; Immune; Immune Response Genes; Immune checkpoint inhibitor; Immune signaling; Immune system; Immunobiology; Immunologic Surveillance; Immunologics; Immunotherapeutic agent; Immunotherapy; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Interferon Type I; Knock-out; Knockout Mice; Link; Malignant - descriptor; Malignant Glioma; Measures; Mediating; Modeling; Molecular Profiling; Mus; Mutate; Mutation; Natural Immunity; Operative Surgical Procedures; Patients; Poly ICLC; Primary Brain Neoplasms; Production; Protein Deficiency; Proteins; RNA; Radiation; Radiation therapy; Relapse; Role; SWI/SNF Family Complex; Signal Transduction; Specimen; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tissues; Tumor Escape; Tumor Immunity; Work; cancer type; chemotherapy; chromatin remodeling; cohort; cytokine; effective therapy; immune activation; immune cell infiltrate; in vivo; inhibitor; innovation; insight; link protein; member; mutant; neoplastic cell; nondeletion type alpha-thalassemia/mental retardation syndrome; 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.

摘要 胶质瘤包括少突胶质细胞瘤和星形细胞瘤亚型，是一组多样化的恶性原发性胶质瘤， 脑肿瘤对放疗、手术和化疗有反应;然而，复发仍然是一个主要障碍 影响患者的总体存活率。针对适应性免疫系统的免疫治疗，如检查点 抑制剂在神经胶质瘤中显示出有限的功效。因此，了解神经胶质瘤的免疫生物学， 对免疫疗法的抗性机制对于治疗性地利用免疫系统以 治疗病人我们的长期目标是解剖神经胶质瘤中的先天免疫系统并找出其弱点 可以用来设计治疗方法。 最近的研究表明，ATRX（一种SWI-SNF染色质重塑剂）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 提示神经胶质瘤中ATRX失活导致丰富的炎性信号和I型胶原的增强， 干扰素/促炎信号传导，以及肿瘤对基于双链（dsRNA）的 免疫激动剂基于这些初步发现，我们假设ATRX失活诱导先天性 炎症并使肿瘤对免疫监视和dsRNA激动剂治疗敏感;并发IDH 突变抑制先天性炎症，使肿瘤免疫逃避。我们将测试我们的假设在 具体目标。目的1：确定ATRX失活在调节胶质瘤细胞内在先天性 目的2：阐明ATRX缺陷和并发IDH 1 R132 H突变在调节抗- 在临床前鼠神经胶质瘤模型中的肿瘤免疫和对dsRNA激动剂治疗的应答;目的3： 确定基于dsRNA的治疗诱导低级别胶质瘤炎症激活的程度。 我们的建议将：1）阐明ATRX损失在调节先天免疫信号反应中的新作用 以及它们在胶质瘤中的下游效应，2）检查ATRX突变和 其伴侣突变IDH 1 R132 H和3）为利用潜在的治疗弱点奠定了临床前基础 携带ATRX突变的神经胶质瘤。