Translation of commensal bacteria mechanism for immunotherapy

共生菌免疫治疗机制的转化

基本信息

批准号：
10064132
负责人：
Howard C Hang
金额：
$ 19.7万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-02 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064132
关键词：
Animal Model Attenuated Bacteria Cancer Model Cancer Patient Cell Wall Cells Chemicals Disease Disseminated Malignant Neoplasm Endopeptidases Engineered Probiotics Engineering Enterococcus Enterococcus durans Enterococcus faecium Enzymes Growth Health Human Immune Immune checkpoint inhibitor Immune response Immune signaling Immunity Immunotherapy Individual Laboratories Large-Scale Sequencing Link Livestock Malignant Neoplasms Malignant neoplasm of lung Metastatic Melanoma Molecular Pathway interactions Patients Pattern recognition receptor Peptidoglycan Population Probiotics Renal carcinoma Resistance Role Signal Pathway Therapeutic Therapeutic Agents Translating Translations Work analog anti-CTLA4 anti-PD-1/PD-L1 anti-PD-L1 therapy anti-PD1 therapy base cancer immunotherapy cancer therapy checkpoint therapy clinical efficacy commensal bacteria drug mechanism enteric infection enteric pathogen host microbiota human model immunoregulation improved in vivo inflammatory disease of the intestine intestinal barrier lactic acid bacteria melanoma microbiota mouse model novel novel therapeutic intervention novel therapeutics patient response pet animal protective factors response small molecule therapy outcome

项目摘要

PROJECT SUMMARY Microbiota are associated with remarkable effects on host health and disease. Notably, discrete species of commensal bacteria have been correlated with improved patient responses to cancer immunotherapy. However, the molecular mechanisms underlying the functions of these beneficial bacteria remain poorly understood. In particular, specific strains of Enterococci have been linked with improved response to anti-PD-1/PD-L1 treatment in patients with metastatic melanoma, lung, and kidney cancers, but their mechanism of action has not been elucidated nor employed to improve cancer immunotherapy. Recent work from the Hang laboratory has demonstrated that these beneficial strains of Enterococci have unique peptidoglycan composition and remodeling enzymes. Based on these studies, this project hypothesizes that specific strains of Enterococci may prime innate immune signaling pathways and enhance anti-PD-1/PD-L1 immunotherapy against metastatic cancers. To evaluate the activity and mechanism(s) of Enterococci during immunotherapy as well as co-opt their protective factors for cancer immunotherapy, this proposal will examine how specific Enterococci strains alter cancer growth, immune cell populations, and microbiota composition in mouse models of cancer immunotherapy. In addition, the Hang laboratory will identify Enterococci protective factors and engineer them into existing human probiotics to translate our basic microbiota-cancer immunotherapy findings into novel therapeutic agents. Finally, the Hang laboratory will also synthesize novel immunomodulatory small molecules that activate host pathways used by Enterococci to enhance cancer immunotherapy. These studies will reveal fundamental microbiota- cancer immunotherapy mechanisms and develop new therapeutic strategies and agents to enhance cancer immunotherapy.

项目概要微生物群对宿主健康和疾病具有显着影响。值得注意的是，离散物种共生细菌与改善患者对癌症免疫治疗的反应有关。然而，这些有益细菌功能背后的分子机制仍然知之甚少。在特别是，特定的肠球菌菌株与抗 PD-1/PD-L1 治疗的反应改善有关在转移性黑色素瘤、肺癌和肾癌患者中，但其作用机制尚未明确尚未阐明或用于改善癌症免疫治疗。 Hang 实验室最近的工作证明这些有益的肠球菌菌株具有独特的肽聚糖组成，并且重塑酶。基于这些研究，该项目假设特定的肠球菌菌株可能启动先天免疫信号通路并增强针对转移性的抗 PD-1/PD-L1 免疫治疗癌症。评估免疫治疗期间肠球菌的活性和机制，并选择其癌症免疫治疗的保护因素，该提案将研究特定肠球菌菌株如何改变癌症免疫治疗小鼠模型中的癌症生长、免疫细胞群和微生物群组成。此外，杭实验室将鉴定肠球菌保护因子，并将其工程化到现有的人体中。益生菌将我们的基本微生物群癌症免疫治疗发现转化为新型治疗剂。最后， Hang实验室还将合成激活宿主途径的新型免疫调节小分子肠球菌用于增强癌症免疫治疗。这些研究将揭示基本的微生物群癌症免疫治疗机制并开发新的治疗策略和药物以增强癌症免疫疗法。