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

摘要： 胃肠道（GI）中的微生物在维持代谢过程中起着关键作用。 和人体免疫系统的健康。微生物群对当地环境的影响 全身免疫越来越被认为是一种重要的调节剂， 免疫疗法的成功，包括针对癌症的免疫疗法。比如说， 无菌动物定植有来自癌症患者的微生物， 对免疫检查点抑制剂（ICI）的应答（应答者- R）显示增强 ICI治疗后肿瘤清除率与微生物定植动物相比 来自无应答患者（无应答者- NR）。其中一种生物 与R型患者相关的是专性厌氧菌 嗜粘蛋白阿克曼氏菌，可能有助于抑制粘膜炎症 和调节全身免疫。对于癌症免疫疗法，重要的是， 曲霉嗜粘蛋白的小鼠模型足以增强ICI的有效性， 肾细胞癌（RCC）和非小细胞肺癌。我们建议调查 临床多样性A.在两个独特的患者群体中的嗜粘蛋白分离物（一个 一个集中在癌症上，另一个集中在代谢疾病上），测试它们在小鼠模型中的影响， 癌症免疫疗法，并将Akkermansia分子遗传学的新工具应用于 定义各种A的贡献。嗜粘蛋白因子在成功抗肿瘤中的作用 疗法 我们希望在这项研究结束时，我们将确定菌株与 最大的潜力作为“佐剂”的ICI和定义的遗传基础， 负责增强活动的特征。鉴于目前的商业利益 作为益生菌，我们设想了一种相对快速的途径， 识别和/或工程化到可以快速跟踪用于临床使用的生物学。

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.