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 ?? T cells in lung tumorigenesis, (2) determine the effector mechanism(s) of ?? 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.