Determining how the human gut microbiota modulates colon cancer tumorigenesis

确定人类肠道微生物群如何调节结肠癌肿瘤发生

• 批准号: 10215257
• 负责人: ALLISON WEIS
• 金额: $ 7.05万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215257
• 关键词: Antibodies; Automobile Driving; Bacteria; Biological Markers; Cancer Model; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Clinical Research; Collection; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Communities; DNA; Data; Development; Diagnostic; Disease; Disease Outcome; Environment; Genes; Genomics; Germ-Free; Gnotobiotic; Health; Human; Human Genetics; Immune; Immune response; Immunoglobulin A; Immunology; Immunotherapy; Inflammation; Intestines; Investigation; Laboratory Research; Lead; Malignant Neoplasms; Mediating; Mentors; Microbe; Mucous Membrane; Mus; National Research Service Awards; Organism; Pathology; Postdoctoral Fellow; Research; Research Personnel; Research Project Grants; Role; Scientist; Secretory Immunoglobulin A; Severities; T-Lymphocyte Subsets; Techniques; Testing; Training; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; United States National Institutes of Health; Universities; Utah; Work; Zoonoses; anti-tumor immune response; bacterial community; cancer type; colon cancer patients; colon cancer treatment; colon tumorigenesis; colorectal cancer treatment; commensal bacteria; commensal microbes; cytotoxic; cytotoxicity; diagnostic biomarker; effector T cell; epidemiology study; experimental study; fecal microbiota; gut bacteria; gut microbiome; gut microbiota; host colonization; host-microbe interactions; human microbiota; humanized mouse; immunogenic; innovation; insight; medical schools; member; microbial; microbiota; mouse model; novel; novel diagnostics; pathogen; pathogenic bacteria; pre-clinical; recruit; response; transmission process; tumor; tumor microenvironment; tumorigenesis; tumorigenic

ABSTRACT Colorectal cancer (CRC) is the third most common cancer worldwide with nearly 1.4 million new cases every year, and rates are predicted to double. Emerging clinical, epidemiological and laboratory research has demonstrated an important role for gut bacteria in CRC development; however, research in this field is lacking and only a few members of the human gut microbiota have been investigated. In addition to exacerbating CRC development, microbes impact the development of effector T cell subsets that influence tumor killing. Colon tumors are often infiltrated by immune cells and disease outcome is influenced by which immune cells are recruited to tumors and their roles within the tumor microenvironment. Despite advances in other cancer types, targeted immunotherapies for colon cancer treatment have been largely unsuccessful. The microbiota could be a major factor in causing CRC and in unsuccessful immunotherapies. Therefore, I hypothesize that differences between the gut microbiotas in healthy and CRC patients contribute to CRC development and severity. To test this hypothesis, I will initially determine if the gut microbiota from human CRC patients has an effect on tumorigenesis in mouse models of CRC by colonizing Germ Free mice with the fecal microbiotas from CRC patients and matched healthy controls, and inducing CRC using an established pre-clinical mouse model for CRC. This aim will identify bacteria that modulate CRC by either exacerbation of tumorigenesis or protection from CRC. I further aim to characterize tumor infiltrating lymphocytes (TILs) within the tumor microenvironment during CRC models, and test the potential of immunogenic bacteria to increase targeted anti-tumor activity, or mitigate tolerogenic responses that hinder anti-tumor cytotoxicity, using both known and undiscovered human-derived bacteria isolated from this study. These experiments will identify novel mechanisms by which bacteria interact with TILs during CRC, and could lead to innovative immunotherapies for CRC. Lastly, I will test the hypothesis that secretory IgA sculpting, or the selection of commensal bacteria by IgA recognition, can lead to detrimental consequences by selecting for pro-tumorigenic bacteria in the colonic mucosa. These experiments will test if IgA sculpting is a mechanism by which pro-tumorigenic bacteria colonize the host. Together, results from this study will identify previously unknown bacteria as important during CRC, leading to new biomarkers and diagnostics, illuminating new strategies for immunotherapy, and gaining novel insight on the dynamic interplay between host and microbe.

摘要 结直肠癌(CRC)是世界上第三常见的癌症，有近140万人 每年都有新病例，预计发病率还会翻一番。新兴的临床、流行病学和 实验室研究表明，肠道细菌在结直肠癌的发展中起着重要作用； 然而，这一领域的研究还很缺乏，人类肠道微生物区系中只有几个成员有 被调查过了。除了加剧结直肠癌的发展外，微生物还会影响结直肠癌的发展 影响肿瘤杀伤的效应T细胞亚群。结肠肿瘤常因免疫系统而被侵袭。 细胞和疾病结局受哪些免疫细胞被招募到肿瘤及其作用的影响 在肿瘤微环境中。尽管在其他癌症类型方面取得了进展，但有针对性的 免疫疗法治疗结肠癌在很大程度上是不成功的。微生物区系可能 是导致结直肠癌和免疫治疗失败的主要因素。因此，我假设 健康人和结直肠癌患者肠道微生物区系的差异与结直肠癌的发病有关 发展和严重程度。 为了验证这一假设，我将首先确定来自人类结直肠癌患者的肠道微生物群 用粪便定植无菌小鼠对结直肠癌小鼠肿瘤形成的影响 来自结直肠癌患者和匹配的健康对照的微生物群，并使用一种 建立结直肠癌临床前小鼠模型。这一目标将通过以下方式识别调节CRC的细菌 要么加剧肿瘤形成，要么保护免受结直肠癌的侵袭。我的进一步目标是描述肿瘤的特征 结直肠癌模型期间肿瘤微环境中的淋巴细胞(TIL)，并检测 免疫原菌提高靶向抗肿瘤活性或减轻耐受性的潜力 使用已知和未发现的人类来源的，阻碍抗肿瘤细胞毒性的反应 从这项研究中分离出的细菌。这些实验将确定细菌通过哪些新机制 在结直肠癌期间与TIL相互作用，并可能导致结直肠癌的创新免疫疗法。 最后，我将检验分泌型免疫球蛋白A雕刻或共生选择的假设 细菌经IgA识别，可通过选择促肿瘤致癌物质而导致有害后果 结肠粘膜中的细菌。这些实验将测试IgA雕刻是否是一种 促进肿瘤的细菌在宿主上定居。总而言之，这项研究的结果将确定之前 未知细菌在结直肠癌中的重要性，导致新的生物标志物和诊断，具有启发性 免疫治疗的新策略，并对宿主之间的动态相互作用获得新的见解 和微生物。