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

抽象/总结

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.