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) 中的微生物在维持新陈代谢方面发挥着关键作用以及人类宿主的免疫健康。微生物群对当地的影响。和系统免疫越来越被认为是一个重要的调节剂免疫疗法的成功，包括针对癌症的免疫疗法。无菌动物被来自癌症患者的微生物群定殖对免疫检查点抑制剂 (ICI) 做出反应（反应者 - R）显示出增强与微生物群定植的动物相比，ICI 治疗后肿瘤的清除率源自没有反应的患者（无反应者 - NR）的生物体之一。与 R 患者一致相关的是专性厌氧菌 Akkermansia muciniphila，可能有助于抑制粘膜炎症和调节全身免疫对于癌症免疫治疗和给药很重要。 A. muciniphila 足以增强 ICI 在小鼠模型中的有效性我们建议对肾细胞癌（RCC）和非小细胞肺癌进行调查。两个独特患者群体中临床 A. muciniphila 分离株的多样性（其中一个专注于癌症和代谢疾病），测试它们对小鼠模型的影响癌症免疫疗法，并应用阿克曼氏菌分子遗传学的新工具定义各种 A. muciniphila 因子对成功抗肿瘤的贡献治疗。我们预计，到本研究结束时，我们将鉴定出具有以下特征的菌株：用作 ICI“佐剂”的最大潜力，并确定了一些的遗传基础考虑到当前的商业利益，这些特征导致了它们的增强活动。关于阿克曼氏菌作为益生菌，我们设想了一种相对快速的菌株消除途径鉴定和/或工程化可快速用于临床的生物制品。