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.

抽象的 神经胶质瘤，包括少突胶质瘤和星形胶质细胞瘤亚型，是一组多种恶性原发性 对放射线，手术和化学疗法反应的脑肿瘤；但是，复发仍然是一个主要的障碍 影响整体患者生存。靶向适应性免疫系统（例如检查点）的免疫疗法 抑制剂在神经胶质瘤中的疗效有限。因此，了解神经胶质瘤的免疫生物学和 对免疫疗法的耐药机制对于在治疗上利用免疫系统至关重要 治疗患者。我们的长期目标是剖析神经胶质瘤的先天免疫系统并确定漏洞 可以利用这用于设计疗法。 最近的研究暗示了ATRX中突变，SWI-SNF染色质重塑剂和 ATRX突变的星形胶质细胞瘤的肿瘤微环境中的免疫细胞浸润。我们的初步数据 建议胶质瘤中的ATRX失活导致富含炎症的特征和I型增强 干扰素/促炎信号传导以及对基于双链（DSRNA）的肿瘤的选择性敏化 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 炎症并使肿瘤对免疫监测和DSRNA激动剂治疗敏感；并发IDH 突变抑制先天的炎症以促进肿瘤免疫逃避。我们将在 遵循特定目标。 AIM 1：定义ATRX失活在调节神经胶质瘤细胞内部先天性中的作用 信号传导； AIM 2：阐明ATRX缺乏症和并发IDH1R132H突变在调节抗抗液中的作用 肿瘤免疫和对临床前鼠神经胶质瘤模型中DSRNA激动剂治疗的反应；目标3： 确定基于DSRNA的疗法在多大程度上诱导下级神经胶质瘤的炎症激活。 我们的建议将：1）描述ATRX损失在调节先天免疫信号反应中的新作用 以及它们在神经胶质瘤中的下游影响，2）检查ATRX突变与 它的伴侣突变，IDH1R132H和3）为利用潜在治疗脆弱性的临床前基础工作 在带有ATRX突变的胶质瘤中。