Varicella virus antigens in glioma etiology and survival

描述（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什么进展。此外，除了电离辐射的作用和少数构成性遗传多态性外，对胶质瘤的病因知之甚少。最近在神经胶质瘤中发现的一系列额外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的过敏较少，水痘病毒相关疾病的发病率较低，并且过敏相关的IgE和细胞因子水平发生改变。大脑具有非常强的免疫调节特性，炎症诱导条件可能会损害大脑，因为它的密闭环境。大脑的免疫特权地位意味着中枢神经系统的肿瘤免疫监视机制尚不清楚；然而，具有趋向性和进入中枢神经系统的致病病毒为指导免疫应答在中枢神经系统恶性肿瘤中的作用提供了线索。水痘病毒（VZV）是一种嗜神经病毒，据推测，针对该病毒的免疫反应可能有助于脑肿瘤的免疫监测。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（使用诊断前血清）和胶质瘤生存（使用诊断后血清）中的抗体反应中的作用。诊断前标本来自前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验（PLCO, N = 129例，对照516例）的参与者，诊断后标本来自旧金山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）。我们将测试针对构成VZV基因组的所有69种蛋白质的特异性抗VZV反应，以比较胶质瘤病例和对照组之间抗原库的特性和强度。我们将通过评估每个VZV抗原之间的病例对照差异以及胶质瘤诊断前（PLCO）和胶质瘤生存期（UCSF AGS）的病例状态来表征这种抗原反应。我们还将使用包括随机森林和partDSA在内的多变量分析技术构建多vzv抗原谱。对于前4个信息性抗原，我们将通过对这些蛋白进行完整的线性表位定位来进一步表征抗原特异性。我们还将使用PLCO预诊断病例（N = 39）和对照（N = 78）评估这些抗vzv反应随时间的变异性，其中5例连续收集（间隔1年）抽血血清可用。蛋白和肽水平的抗vzv反应将为胶质瘤病因和可能与胶质瘤抗原交叉反应的单个抗原提供线索，从而增强对胶质瘤形成中的免疫反应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.