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