The impact of genetic diversity among Akkermansia strains on the effectivenes of immune checkpoint inhibitors in cancer immunotherapies

摘要： 胃肠道(GI)中的微生物在维持新陈代谢方面起着关键作用。 和人类宿主的免疫健康。微生物区系对当地环境的影响 而系统免疫越来越被认为是一种重要的 免疫疗法的成功，包括针对癌症的免疫疗法。例如, 带有来自癌症患者的微生物的无菌动物 对免疫检查点抑制剂(ICI)的反应(响应者-R)显示增强 ICI治疗肿瘤的清除率与寄生微生物的动物的比较 来自无应答的患者(无应答-NR)。其中一种生物体 与R患者一致相关的是专性厌氧菌 粘性阿克曼原虫，可能有助于抑制粘膜炎症 和调节系统免疫力。对癌症免疫治疗很重要，给药 粘液嗜酸杆菌足以增强ICIS在小鼠模型中的有效性 肾细胞癌(RCC)和非小细胞肺癌。我们建议对 两个独特的患者群体(一个)中临床粘液葡萄球菌分离株的多样性 专注于癌症和代谢性疾病)，在小鼠模型上测试它们的影响 癌症免疫治疗，并应用阿克曼西亚分子遗传学的新工具 明确各种粘液葡萄球菌因子(S)在成功抗肿瘤中的作用 心理治疗。 我们预计在这项研究结束时，我们将鉴定出与 作为ICI的“佐剂”的最大潜力，并确定了一些 导致它们活动增强的特征。鉴于目前的商业利益 关于阿克曼氏菌作为益生菌，我们设想了一条相对快速的从菌株 鉴定和/或工程到可以快速追踪用于临床的生物。

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.