Varicella virus antigens in glioma etiology and survival

描述（由申请人提供）：胶质瘤是最致命的成人癌症之一;在过去的30年里，临床研究人员在治疗成功方面几乎没有取得进展。此外，除了电离辐射的作用和少数组成性遗传多态性外，对胶质瘤的病因了解甚少。最近在神经胶质瘤中的一系列发现与免疫因素的作用有关：与健康对照相比，神经胶质瘤患者报告较少的过敏和较低的水痘病毒相关疾病的频率，并且具有改变的过敏相关IgE和细胞因子水平。大脑具有非常强的免疫调节特性，并且由于其封闭的环境，炎症诱导条件可能损害大脑。大脑的免疫特权状态意味着CNS中的肿瘤免疫监视机制知之甚少;然而，具有嗜性和进入CNS的致病性病毒提供了线索，以指导研究免疫应答在CNS恶性肿瘤中的作用。水痘病毒（VZV）是一种嗜神经性病毒，据推测，针对该病毒的免疫应答可能有助于脑肿瘤的免疫监视。为了探索这一前提，我们将研究特异性VZV抗原在阐明胶质瘤病因学（使用诊断前血清）和胶质瘤生存（使用诊断后血清）中的抗体应答中的作用。诊断前样本来自前列腺、肺、结直肠和卵巢癌筛查试验（PLCO，N = 129例病例和516例对照）中嵌套的参与者，诊断后样本来自旧金山弗朗西斯科湾区成人胶质瘤研究（UCSF AGS，N = 1000例胶质瘤病例，具有完整的治疗和肿瘤数据）中的病例。我们将测试针对所有69种蛋白质的特异性抗VZV反应，这些蛋白质构成VZV基因组，以比较胶质瘤病例和对照之间抗原库的身份和强度。我们将通过评估胶质瘤诊断前（PLCO）和胶质瘤生存期（UCSF AGS）中每种VZV抗原与病例状态之间的病例对照差异来表征这种抗原应答。我们还将使用多变量分析技术（包括随机森林和partDSA）构建多VZV抗原谱。对于前4个信息抗原，我们将通过对这些蛋白质进行完整的线性表位作图来进一步表征抗原特异性。我们还将使用PLCO诊断前病例（N = 39）和对照（N = 78）评估这些抗VZV应答随时间的变化，其中5份连续采集（间隔1年）的抽血血清可用。蛋白质和肽水平的抗VZV应答将为胶质瘤病因学和可能与胶质瘤抗原交叉反应的个体抗原提供线索，从而增强对胶质瘤形成中的免疫应答及其临床相关性的理解。

DESCRIPTION (provided by applicant): Gliomas are among the most deadly adult cancers; clinical researchers have made few gains in treatment success in the past 30 years. In addition, there is little understanding about the causes of glioma apart from the role of ionizing radiation and a small number of constitutive genetic polymorphisms. An additional recent array of findings in gliomas is related to the role of immune factors: when compared to healthy controls glioma patients report fewer allergies and lower frequencies of varicella-virus-related diseases, and have altered levels of allergy-related IgE and cytokines. The brain has very strong immunomodulatory properties, and inflammation-inducing conditions may damage the brain due to its confined environment. The immune privileged status of the brain means that tumor immunosurveillance mechanisms in the CNS are poorly understood; however, pathogenic viruses with tropism and access to the CNS provide clues to guide research on the role of immune response in CNS malignancies. Varicella Virus (VZV) is a neurotropic virus, and it is hypothesized that an immune response against the virus may facilitate immunosurveillance of brain tumors. To explore this premise, we will investigate the role of specific VZV antigens in elucidating antibody responses in glioma etiology (using pre-diagnostic sera) and in glioma survival (using post-diagnostic sera). Pre- diagnostic specimens are from participants nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, N = 129 cases, and 516 controls), and post-diagnostic are from cases in the San Francisco Bay Area Adult Glioma Study (UCSF AGS, N = 1000 glioma cases with complete treatment and tumor data). We will test for specific anti-VZV response against all 69 proteins that comprise the VZV genome to compare identities and intensities of the antigenic repertoire between glioma cases and controls. We will characterize this antigen response by assessing case-control differences between each individual VZV antigen and case status both before diagnosis of glioma (PLCO) and in glioma survival (UCSF AGS). We will also construct multi-VZV-antigen profiles using multivariable analytic techniques including random forests and partDSA. For the top 4 informative antigens, we will further characterize antigenic specificity by performing a complete linear epitope mapping of those proteins. We will also assess variability in these anti-VZV responses over time using PLCO pre-diagnostic cases (N = 39) and controls (N = 78) for whom 5 serially collected (at 1 year intervals) blood draw sera are available. Anti-VZV responses at the protein and peptide level will provide clues to glioma etiology and possibly individual antigens that cross-react with glioma antigens, providing an enhanced understanding of immune response in gliomagenesis and its clinical relevance.