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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的：胃肠道（GI）中的微生物在维持代谢中起着至关重要的作用和人类宿主的免疫健康。微生物群对局部的影响系统的免疫力越来越被认为是免疫疗法的成功，包括针对癌症的人。例如，源自癌症患者的微生物群定植的无细菌动物，对免疫检查点抑制剂（ICI）的响应（响应者-R）显示了增强与用菌群定殖的动物相比，ICI治疗时肿瘤清除率源自未反应的患者（非反应者-NR）。其中一种生物与R患者保持一致的是厌氧细菌 akkermansia粘膜，这可能导致粘膜发炎并调节系统性免疫疗法。重要的是癌症免疫疗法，给药粘曲霉的曲霉足以提高ICI在小鼠模型中的有效性肾细胞癌（RCC）和非小细胞肺癌。我们建议调查两个独特的患者种群中临床A. muciniphila分离株的多样性（一个专注于癌症，一种用于代谢疾病），测试其在小鼠模型中的影响癌症免疫疗法，并在Akkermansia分子遗传学中应用新工具定义各种粘膜粘脂质因子对成功抗肿瘤的贡献治疗。我们希望在这项研究结束时，我们将确定与用作ICI的“佐剂”的最大潜力，并定义了某些的遗传基础负责其增强活动的特征。鉴于当前的商业利益在Akkermansia作为益生菌上，我们设想了相对较快的菌株路径可以快速跟踪临床使用的生物学的识别和/或工程。