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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：
10379772
负责人：
Howard C Hang
金额：
$ 34.9万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379772
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.

项目总结微生物区系对寄主健康和疾病有显著的影响。值得注意的是，离散的物种共生细菌与癌症免疫治疗患者反应的改善有关。然而，这些有益细菌的功能背后的分子机制仍然知之甚少。在……里面特别是，特定的肠球菌株与抗PD-1/PD-L1治疗的改善反应有关在转移性黑色素瘤、肺癌和肾癌患者中，但它们的作用机制尚未得到证实既未阐明也未用于改进癌症免疫治疗。Hang实验室最近的工作是证明这些有益的肠球菌具有独特的肽聚糖组成和重塑酶。基于这些研究，该项目假设特定的肠球菌菌株可能启动天然免疫信号通路加强抗PD-1/PD-L1免疫治疗抗转移癌症。肠球菌在免疫治疗中的活性和作用机制(S)的评价及其相互作用癌症免疫治疗的保护因素，这项建议将检查特定肠球菌株如何改变肿瘤免疫治疗小鼠模型中的肿瘤生长、免疫细胞种群和微生物区系组成。此外，Hang实验室将识别肠球菌保护因素，并将它们改造到现有的人类体内益生菌将我们的基本微生物区系癌症免疫治疗结果转化为新的治疗剂。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来加强癌症免疫治疗。这些研究将揭示基本的微生物区系- 癌症免疫治疗机制和开发新的治疗策略和制剂以增强癌症免疫疗法。