Translation of commensal bacteria mechanism for 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。

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.