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

摘要 胶质瘤，包括少突胶质细胞瘤和星形细胞瘤亚型，是一种不同类型的原发恶性肿瘤。 对放射、手术和化疗有反应的脑瘤；然而，复发仍然是一个主要障碍 影响患者的总体生存。针对适应性免疫系统的免疫治疗，如检查点 抑制剂在脑胶质瘤中的疗效有限。因此，了解胶质瘤的免疫生物学和 抵抗免疫疗法的机制对于在治疗上利用免疫系统 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，并找出弱点。 这可以被用来设计治疗方法。 最近的研究表明，SWI-SNF染色质重构体ATRX的突变与 ATRX突变型星形细胞瘤微环境中免疫细胞的浸润我们的初步数据 提示脑胶质瘤中ATRX失活可导致丰富的炎性信号和I型的增强 干扰素/促炎信号转导和肿瘤对双链(DsRNA)的选择性增敏 免疫激动剂。根据这些初步发现，我们假设ATRX失活导致先天 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，使肿瘤免疫逃逸。我们将在 遵循特定的目标。目的1：确定ATRX失活在调节胶质瘤细胞固有特性中的作用 目的2：阐明ATRX缺乏和IDH1R132H突变在调节抗 临床前小鼠胶质瘤模型中的肿瘤免疫和对dsRNA激动剂治疗的反应；目的3： 确定基于dsRNA的治疗在多大程度上诱导低级别胶质瘤的炎症激活。 我们的建议将：1)描绘ATRX缺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ATRX基因突变之间的免疫相互作用 它的伙伴突变IDH1R132H和3)为开发潜在的治疗脆弱性奠定了临床前基础 在携带ATRX突变的胶质瘤中。

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.