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: 9978547
• 负责人: ALLISON WEIS
• 金额: $ 6.74万
• 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/9978547
• 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）是全球第三大常见癌症， 每年都有新的病例，预计发病率将翻一番。新兴的临床、流行病学和 实验室研究已经证明肠道细菌在CRC发展中的重要作用; 然而，在这一领域的研究是缺乏的，只有少数成员的人类肠道微生物群 被调查了除了加剧CRC的发展，微生物还影响CRC的发展。 影响肿瘤杀伤的效应T细胞亚群。结肠肿瘤经常被免疫细胞浸润， 细胞和疾病结果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，但针对 用于结肠癌治疗的免疫疗法在很大程度上不成功。微生物群可以 是导致CRC和免疫治疗失败的主要因素。因此，我假设 健康和CRC患者肠道微生物之间的差异有助于CRC 发展和严重性。 为了验证这一假设，我将首先确定人类CRC患者的肠道微生物群是否 通过用粪便定殖无菌小鼠， 来自CRC患者和匹配的健康对照的微生物群，并使用 建立CRC临床前小鼠模型。这一目标将确定细菌调节CRC， 或者加重肿瘤发生或者保护免于CRC。我进一步的目标是描述肿瘤 在CRC模型期间肿瘤微环境内的浸润淋巴细胞（TIL），并测试 免疫原性细菌增加靶向抗肿瘤活性或减轻致耐受性的潜力 使用已知的和未发现的人源性的抗肿瘤细胞毒性， 从这项研究中分离的细菌。这些实验将确定新的机制， 在CRC期间与TIL相互作用，并可能导致CRC的创新免疫疗法。 最后，我将测试的假设，分泌型伊加雕塑，或选择的唾液酸 通过伊加识别细菌，可以通过选择促肿瘤发生而导致有害后果。 结肠粘膜中的细菌。这些实验将测试伊加雕刻是否是一种机制， 促肿瘤发生细菌在宿主中定植。总之，这项研究的结果将确定以前 未知的细菌在CRC期间很重要，导致新的生物标志物和诊断， 免疫治疗的新策略，并获得对宿主之间动态相互作用的新见解 和微生物。