Investigating immune-microbiota interaction in lung cancer

项目总结/摘要 共生微生物群栖息在多个人体部位，主要在肠中，并且还沿着肠壁。 呼吸道，包括肺。肠道微生物群已经成为肠道微生物的重要调节因子。 在几种癌症中的肿瘤发生和治疗反应，但其在肺癌中的作用尚不清楚 明白肺部微生物群的变化与几种肺部疾病有关;细菌性 感染在肺癌患者中非常常见，与临床结果密切相关，但 其背后的生物学原理一直难以捉摸。因此，本研究旨在探讨局部（肺） 和远端（肠道）微生物群在肺癌发展中的作用 其重现了人肺腺癌中Kras激活点突变和p53缺失。我们 初步结果表明，肿瘤生长与细菌负荷增加有关， 微生物群的全身消耗显著减少了炎症， 和肿瘤负荷，这表明紊乱的微生物群的发展可能会诱导失调的微生物群。 免疫应答促进肺癌进展。在这里，我们建议进一步询问复杂的 肠道微生物群，宿主免疫系统和发育中的肿瘤细胞之间的相互作用，以阐明 微生物群促进肿瘤发生和发展的细胞和分子机制。 具体而言，我们将（1）确定微生物群诱导的γδ T细胞在肺肿瘤发生中的作用，（2）确定 γδ T细胞在介导微生物群驱动的肿瘤促进中的效应机制，（3）确定肿瘤- 促进肺部或肠道微生物群中的细菌。虽然目前的研究旨在揭示 通过塑造肿瘤相关的免疫反应， 该奖项的独立阶段将侧重于确定细菌种类和响应宿主 参与肿瘤促进的途径，其可被靶向用于肺癌的治疗干预。 我的职业目标是独立指导一个学术研究实验室，解决与以下问题有关的问题： 癌症中免疫-微生物群相互作用的生物学和机制。虽然我有丰富的经验， 研究免疫学和微生物群，并使用遗传小鼠模型，该项目的K99阶段将 允许我接受先进的生物信息学和微生物学技能的进一步培训，并开发新的 基因编辑工具在体内使用肺癌的本地小鼠模型。另外，我会利用 麻省理工学院/布罗德研究所提供的极好的培训机会和资源，并进一步建立 与波士顿地区强大的多学科研究社区的合作和网络。这些 建议的培训和研究活动将大大促进我的职业发展，走向独立 免疫微生物群相互作用研究前沿的研究人员，这是一个新兴领域，可以显着 扩展我们对癌症的理解，并为我们提供更有效的癌症治疗方法的指导。

Project Summary/Abstract Commensal microbiota inhabits multiple human body sites, primarily in the intestine, and also along the respiratory tract including the lung. Intestinal microbiota has emerged as an important regulator of tumorigenesis and therapeutic response in several cancers, yet its role in lung cancer has not been clearly understood. Changes in the lung microbiota have been associated with several pulmonary disorders; bacterial infections are highly common in lung cancer patients and closely related to clinical outcomes, but the underlying biology has been elusive. Therefore, the proposed study aims to investigate the role of local (lung) and distal (intestinal) microbiota in lung cancer development by using a genetically-engineered mouse model that recapitulates the activating point mutation of Kras and loss of p53 in human lung adenocarcinoma. Our preliminary results showed that tumor growth was associated with increased bacterial burden and altered microbiota composition in the lung, while systemic depletion of microbiota significantly reduced inflammation and tumor burden, suggesting that the development of a disordered microbiota may induce a dysregulated immune response to promote lung cancer progression. Here we propose to further interrogate the complex interactions among commensal microbiota, the host immune system and developing tumor cells to elucidate the cellular and molecular mechanism(s) by which microbiota promotes tumor initiation and progression. Specifically, we will (1) establish the role of microbiota-induced γδ T cells in lung tumorigenesis, (2) determine the effector mechanism(s) of γδ T cells in mediating microbiota-driven tumor promotion, (3) identify the tumor- promoting bacteria in the lung or intestinal microbiota. While the current research aims to reveal the role of commensal microbiota in lung cancer by shaping the tumor associated immune response, continued efforts in the independent phase of this award will be focused on identifying the bacterial species and responding host pathways involved in tumor promotion which may be targeted for therapeutic intervention in lung cancer. My career goal is to independently direct an academic research laboratory addressing questions pertaining to the biology and mechanism of immune-microbiota interaction in cancer. While I have extensive experience in studying immunology and microbiota, and the use of genetic mouse models, the K99 phase of this project will allow me to receive further training in advanced bioinformatics and microbiology skills, and to develop novel gene-editing tools in vivo using autochthonous mouse models of lung cancer. Moreover, I will take advantage of the superb training opportunities and resources available at the MIT/Broad Institute and further establish collaborations and networks with the strong, multidisciplinary research communities in the Boston area. These proposed training and research activities will greatly promote my career development towards an independent investigator in the frontier of research on immune-microbiota interaction, a rising field that can significantly extend our understanding of cancer and provide us guidance towards more effective cancer therapies.