Multi-strain, live biotherapeutics as adjuncts to checkpoint inhibitor therapy

项目摘要 最近的一系列研究强调了肠道微生物群组成作为一个因素的重要性 确定检查点抑制剂疗法治疗多种癌症的功效。这些研究发现， 一些在遗传学上不相关的分类群，在报告中缺乏一致性，造成混乱， 怀疑论在这个领域。我们评估了益生元（菊粉和粘蛋白）的效果，发现这些治疗 诱导肠道微生物群组成的改变，并导致一些但不是所有的肿瘤生长减弱。 肿瘤模型测试与有效肿瘤控制相关的小鼠的微生物群谱与那些与有效肿瘤控制相关的小鼠的微生物群谱的比较 这表明，编码抗肿瘤表型的细菌物种富含大量的 不同的系统进化枝。类似地，我们观察到抗肿瘤分类群与不同的细胞因子正相关。 TILs谱表明能够刺激多种抗肿瘤免疫的优化的细菌鸡尾酒， 反应可以允许更稳健的肿瘤生长控制。我们将测试菊糖喂养是否能恢复肿瘤控制 来自对检查点抑制剂无反应的患者的粪便微生物群定殖的gnotobiotic小鼠 疗法我们有能力从事翻译工作，以隔离和验证 相关的系统发生组，以确定促进对检查点抑制剂的反应性改善的分类群， 这是开发用于人类患者的优化益生菌制剂的重要一步。我们将探讨 菊糖赋予抗肿瘤免疫能力的机制方面，我们将进行代谢组学分析， 用确定的、低复杂性的群落和体外培养物定殖的无菌小鼠来鉴定菊粉， 依赖性代谢物，其可以向肠道免疫系统发出信号以诱导抗肿瘤免疫。

PROJECT SUMMARY A series of recent studies have highlighted the importance of the composition of the gut microbiota as a factor determining the efficacy of checkpoint inhibitor therapy to treat a variety of cancers. These studies have identified a number of phylogenetically unrelated taxa that lack consistency across reports, generating confusion and skepticism in the field. We evaluated the effect of prebiotics (inulin and mucin) and found that these treatments induce alterations in gut microbiota composition and lead to tumor growth attenuation in some but not all of the tumor models tested. Comparison of microbiota profiles of mice associated with effective tumor control to those that failed to do so, suggests that bacterial species encoding anti-tumor phenotypes are enriched in a number of distinct phylogenetic clades. Similarly, we observed that anti-tumor taxa are positively correlated with distinct TILs profiles suggesting that an optimized bacterial cocktail capable of stimulating multiple anti-tumor immune responses may allow more robust tumor growth control. We will test whether inulin feeding restores tumor control of gnotobiotic mice colonized with fecal microbiota from patients that were non-responsive to checkpoint inhibitor therapy. We are strongly positioned to engage in translational efforts to target the isolation and validation of relevant phylogenetic groups to identify taxa promoting improved responsiveness to checkpoint inhibitors as an important step toward developing optimized probiotic formulations for use in human patients. We will explore mechanistic aspects of inulin's ability to confer anti-tumor immunity we will conduct metabolomics analyses using gnotobiotic mice colonized with defined, low-complexity communities and in vitro cultures to identify inulin- dependent metabolites that may signal the gut immune system to induce anti-tumor immunity.