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

摘要/摘要 恶性胶质瘤，特别是胶质母细胞瘤(GBM)，是一种高度侵袭性的、无法治愈的脑肿瘤。即使是在 最大限度的手术切除，化疗和放疗，肿瘤复发是绝对的，中位生存期是 大约14个月。免疫治疗策略已在管理方面取得了显著的成功。 多发性实体恶性肿瘤。不幸的是，免疫疗法，特别是检查站封锁，已经取得了有限的效果。 免疫抑制微环境和多重内源性免疫在GBM治疗中的成功 回避机制。解决局部免疫抑制、增强免疫反应的新策略 并提高对免疫疗法的反应性，以改善患者的预后。胆量 微生物组是一种公认的宿主免疫反应的调节器。微生物区系驱动的免疫调节 已被证明对多种恶性肿瘤和干预措施的免疫治疗反应有影响 调节微生物群可以增强治疗反应，改善患者预后。除了肠子之外 微生物组，肿瘤内的微生物组也被证明影响患者对 免疫疗法。微生物组-肠道-脑轴是一个已知的双向通路，具有广泛的 对中枢神经系统的免疫调节影响，包括对功能的直接影响 小胶质细胞。此外，肠道微生物组也被认为与非霍奇金淋巴瘤的发生发展有关。 各种神经疾病。除了肠道微生物组，我们自己和其他人的工作也证明了 GBM患者样本中细菌特征的存在，然而GBM肿瘤的临床影响 微生物组是未知的。尽管微生物组的影响无处不在，但它在中枢神经系统恶性肿瘤中的作用 没有经过评估。我们建议通过系统的、多平台的评估来解决这一知识差距 使用预期收集的临床样本(肿瘤和肠道/粪便)对GBM的微生物成分进行评估。我们会 将这些微生物特征与GBM肿瘤微环境的免疫成分和 患者结局衡量标准。此外，我们将补充我们的临床发现，临床前，免疫功能 GBM小鼠模型检测肠道微生物组缺失对肿瘤生长和肿瘤免疫的影响 微环境。我们的假设是，在GBM中存在不同的肠道和肿瘤微生物特征 患者，有助于肿瘤微环境的构成，并影响患者的预后。我们将对此进行研究 通过以下目标：目标1：确定与改进有关的肠道和肿瘤微生物组特征 GBM患者的预后。目的2：确定微生物组在肾小球基底膜中的免疫调节作用。如果 如果成功，我们将是第一个描述肠道和肿瘤微生物群在恶性胶质瘤中的作用的人。我们的 长期目标是开发新的策略来克服治疗阻力，改善患者的预后。

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.