The impact of genetic diversity among Akkermansia strains on the effectivenes of immune checkpoint inhibitors in cancer immunotherapies

阿克曼氏菌菌株遗传多样性对癌症免疫治疗中免疫检查点抑制剂有效性的影响

• 批准号: 10115682
• 负责人: You-Wen He
• 金额: $ 22.58万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115682
• 关键词: Anaerobic Bacteria; Animals; Biological; Cancer Model; Cancer Patient; Child; Clinical; Collection; Diabetes Mellitus; Effectiveness; Engineering; Epithelial Cell Junction; Foundations; Gastrointestinal tract structure; Genetic; Genetic Variation; Genome; Genomic Segment; Germ-Free; Goals; Hospitals; Human; Immune checkpoint inhibitor; Immunity; Immunization; Immunologic Adjuvants; Immunotherapy; Insertional Mutagenesis; Link; Malignant Neoplasms; Metabolic; Metabolic Diseases; Metastatic Renal Cell Cancer; Microbe; Microbial Biofilms; Molecular Genetics; Monitor; Mucins; Mucositis; Mus; Mutation; Neoadjuvant Therapy; Non-Small-Cell Lung Carcinoma; Obesity; Organism; Outcome; PD-1/PD-L1; Patients; Phenotype; Play; Probiotics; Production; Renal Cell Carcinoma; Role; Sampling; Signal Transduction; Source; Specimen; Surveys; Testing; Therapeutic; Time; Transplantation; Tumor Cell Line; Variant; anti-PD-1; base; beneficial microorganism; cancer immunotherapy; checkpoint therapy; cohort; comparative genomics; defined contribution; design; diet-induced obesity; genomic locus; germ free condition; gut colonization; immune health; improved outcome; interest; intestinal barrier; microbial; microbiota; mouse model; mutant; patient population; response; stool sample; success; tool; trait; tumor

ABSTRACT: Microbes in the gastrointestinal tract (GI) play a critical role in maintaining the metabolic and immunological health of their human hosts. The impact of the microbiota on local and systemic immunity is being increasingly recognized as an important modifier of the success of immunotherapies, including those directed against cancers. For instance, germ free animals colonized with microbiotas derived from cancer patients that responded (responders - R) to immune checkpoint inhibitors (ICI) displayed enhanced clearance of tumors upon ICI therapy as compared to animal colonized with microbiotas derived from patients that did not respond (non responders - NR). One of the organisms that is consistently associated with R patients is the obligate anaerobic bacterium Akkermansia muciniphila, which may contribute to dampening mucosal inflammation and regulating systemic immunity. Importantly for cancer immunotherapy, administration of A. muciniphila is sufficient to enhance the effectiveness of ICIs in mouse models of renal cell carcinomas (RCC) and non-small cell lung cancers. We propose to survey the diversity of clinical A. muciniphila isolates in two unique patient populations (one focused on cancer and one on metabolic disease), test their impact in mouse models of cancer immunotherapy, and apply new tools in Akkermansia molecular genetics to define the contribution of various A. muciniphila factor(s) on successful anti-tumor therapy. We expect that by the end of this study that we will have identified strains with the greatest potential for use as “adjuvants” of ICI and defined the genetic basis of some of the traits responsible for their enhanced activities. Given the current commercial interest on Akkermansia as a probiotic, we envision a relatively rapid path from strain identification and/or engineering to a biological that can be fast-tracked for clinical use.

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