Investigating immune-microbiota interaction in lung cancer

项目摘要/摘要 共生微生物区系分布在人体的多个部位，主要是在肠道中，也沿 呼吸道，包括肺部。肠道微生物区系已成为一种重要的调节因子 几种癌症的肿瘤发生和治疗反应，但其在肺癌中的作用尚不清楚 明白了。肺部微生物区系的变化与几种肺部疾病有关；细菌 感染在肺癌患者中非常常见，并与临床结果密切相关，但 潜在的生物学一直难以捉摸。因此，拟议的研究旨在调查局部(肺)的作用。 和远端(肠道)微生物区系在肺癌发生中的作用 这概括了人肺腺癌中Kras的激活点突变和P53的丢失。我们的 初步结果显示，肿瘤的生长与细菌负荷增加和改变有关。 肺部的微生物区系组成，而全身微生物区系的耗竭显著减少炎症 和肿瘤负担，这表明无序的微生物区系的发展可能会导致 促进肺癌进展的免疫反应。在这里，我们建议进一步审问该建筑群 共生微生物区系、宿主免疫系统和发育中的肿瘤细胞之间的相互作用 微生物区系促进肿瘤发生和发展的细胞和分子机制(S)。 具体地说，我们将(1)确定微生物区系诱导的γδT细胞在肺肿瘤发生中的作用，(2)确定 γδT细胞在微生物区系促癌中的效应机制(S)，(3)鉴定肿瘤- 促进肺部或肠道微生物区系中的细菌。虽然目前的研究旨在揭示 肺癌中的共生微生物群通过塑造肿瘤相关的免疫反应，在 该奖项的独立阶段将集中在鉴定细菌种类和响应宿主上。 参与肿瘤促进的通路，可能成为肺癌治疗干预的靶点。 我的职业目标是独立指导一个学术研究实验室，解决与 肿瘤中免疫-微生物区系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区系，并使用遗传小鼠模型，这个项目的K99阶段将 请允许我接受高级生物信息学和微生物学技能的进一步培训，并开发新的 体内基因编辑工具使用原生小鼠肺癌模型。此外，我还会利用 麻省理工学院/博德学院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合作和建立网络。这些 拟议的培训和研究活动将极大地促进我的职业发展，使我成为一名独立的 处于免疫-微生物相互作用研究前沿的研究人员，这是一个新兴的领域，可以显著 扩大我们对癌症的理解，并为我们提供更有效的癌症治疗方法。

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.