Elucidating the Role of the Gut and Tumor Microbiome in Malignant Glioma

摘要/总结 恶性胶质瘤，特别是胶质母细胞瘤（GBM），是高度侵袭性的，不可治愈的脑肿瘤。即使有 最大的手术切除，化疗和放疗，肿瘤复发是绝对的，中位生存期是 大约14个月。免疫策略在管理 多发性恶性肿瘤不幸的是，免疫疗法，特别是检查点阻断， 由于其免疫抑制微环境和多种内在免疫， 规避机制解决局部免疫抑制、增强免疫应答的新策略 和增强对免疫疗法的反应性是改善患者结果的必要条件。肠道 微生物组是宿主免疫应答的公认调节剂。微生物群驱动的免疫调节 已被证明可影响多种恶性肿瘤和干预措施对免疫治疗的反应， 调节微生物组可以增强治疗反应并改善患者结果。除了内脏 肿瘤内微生物组也已被证明会影响患者对 免疫疗法微生物组-肠-脑-轴是已知的双向途径，具有广泛的 对中枢神经系统（CNS）的免疫调节影响，包括对功能的直接影响 小胶质细胞此外，肠道微生物组也涉及肠上皮细胞癌的发病机制和进展。 各种神经系统疾病。除了肠道微生物组，我们自己和其他人的工作已经证明， GBM患者样本中存在细菌特征，然而GBM肿瘤的临床影响 微生物是未知的。尽管其广泛的影响，微生物组在中枢神经系统恶性肿瘤中的作用， 没有被评估。我们建议通过系统的、多平台的评估来弥补这一知识差距 使用前瞻性收集的临床样品（肿瘤和肠道/粪便）的微生物组成GBM。我们将 将这些微生物特征与GBM肿瘤微环境的免疫组成相关联， 患者结局指标。此外，我们将补充我们的临床发现与临床前，免疫活性 检查肠道微生物组消耗对肿瘤生长和肿瘤免疫的影响的GBM小鼠模型 微环境我们的假设是，不同的肠道和肿瘤微生物的签名存在于GBM 患者，有助于肿瘤微环境的组成和影响患者的结果。我们会研究这个 通过以下目的：目的1：确定与改善相关的肠道和肿瘤微生物组特征 GBM患者的结局。目的2：确定微生物组在GBM中的免疫调节作用。如果 如果成功，我们将是第一个描述肠道和肿瘤微生物组在恶性胶质瘤中的作用的人。我们 长期目标是开发新的策略，以克服治疗阻力，改善患者的结果。

ABSTRACT/SUMMARY Malignant gliomas, specifically glioblastoma (GBM), are highly aggressive, incurable brain tumors. Even with maximal surgical resection, chemotherapy and radiation, tumor recurrence is absolute and median survival is approximately 14 months. Immunotherapeutic strategies have had notable success in the management of multiple solid malignancies. Unfortunately, immunotherapy, particularly checkpoint blockade, has had limited success in the treatment of GBM due to its immunosuppressive microenvironment and multiple intrinsic immune evasive mechanisms. Novel strategies to address local immunosuppression, augment the immune response and enhance responsiveness to immunotherapies are warranted to improve patient outcome. The gut microbiome is a well-established modulator of host immune responses. Microbiota-driven immunomodulation has been demonstrated to impact responses to immunotherapy in multiple malignancies and interventions that modulate the microbiome can enhance treatment response and improve patient outcome. In addition to the gut microbiome, the intra-tumoral microbiome has also been demonstrated to impact patient response to immunotherapy. The microbiome-gut-brain-axis is a known bidirectional pathway with extensive immunomodulatory influence on the central nervous system (CNS) including a direct impact on the functionality of microglia. Further the gut microbiome has also been implicated in the pathogenesis and progression of a variety of neurological conditions. In addition to the gut microbiome, our own work and others have demonstrated the presence of bacterial signatures in GBM patient samples, however the clinical impact of the GBM tumor microbiome is unknown. Despite its pervasive influence, the role of the microbiome in CNS malignancies has not been evaluated. We propose to address this gap in knowledge with a systematic, multi-platform evaluation of the microbial composition GBM using prospectively collected clinical samples (tumor and gut/stool). We will correlate these microbial signatures with both the immune composition of the GBM tumor microenvironment and patient outcome measures. Further, we will compliment our clinical finding with preclinical, immunocompetent GBM mouse model examining the impact of gut microbiome depletion on tumor growth and the tumor immune microenvironment. Our hypothesis is that differential gut and tumor microbial signatures are present in GBM patients, contribute to the tumor microenvironment composition and impact patient outcome. We will study this via the following aims: AIM 1: Determine the gut and tumor microbiome signatures associated with improved outcomes in patients with GBM. AIM 2: Determine the immunomodulatory role of the microbiome in GBM. If successful, we will be the first to describe the role of the gut and tumor microbiome in malignant glioma. Our long-term goal is to develop novel strategies to overcome therapeutic resistance and improve patient outcome.