The role of the intestinal microbiome in cancer immunotherapy

摘要 肠道微生物区系由多种微生物组成，对人类有许多影响。 (病态)生理学。微生物组的组成与许多疾病有关，但因果推断 常常缺乏。临床前和临床研究表明，肠道微生物区系具有天然调节作用。 获得性免疫，包括T细胞和异基因造血细胞后的抗肿瘤免疫 移植(allo-HCT)和检查站封锁。我的实验室一直专注于肠道微生物区系在 异基因血细胞移植和免疫治疗的结果。例如，我们展示了微生物群的组成经历了 在allo-HCT期间显著和频繁的变化，以及较低的肠道微生物区系多样性与 死亡率上升。我们还发现，某些物种的优势种，最常见的肠球菌，是 与致命性移植物抗宿主病(GVHD)有关；暴露于某些抗生素与 异基因血细胞移植和嵌合抗原受体T细胞(CART)治疗后预后较差； 重建与有益菌群的存在有关。这些研究已经转化为临床 使用自体粪便微生物区系移植、给药确定的细菌联合体和抗生素的试验 管理以保护和/或恢复共生植物群。这项提议的首要假设是 肠道微生物组是癌症发生过程中先天免疫和获得性免疫的重要调节器 免疫疗法。虽然免疫疗法在一些接受者中是治愈的，但提高了它们的疗效并减轻了 毒性是肿瘤学中未得到满足的需求。主要目标是通过靶向癌症免疫治疗来改善癌症免疫治疗 基于临床前和临床研究的肠道微生物组。我们正在进行和计划中的研究的例子 包括：a)开发微生物组分析的新管道，b)临床前和临床项目 肠道微生物组和CART，c)分析饮食和药物对肠道影响的新技术 微生物组，以及d)关于胆汁酸免疫调节的临床前和临床研究，例如 我们如何研究肠道微生物群调节免疫和癌症的机制 免疫疗法。我们组织了一个多中心全球联盟来收集粪便样本(单独资助 以及集成患者、微生物组和肿瘤简档的新的多组学方法 使用计算平台(MSK-Mind)进行数据协调和机器学习的模式。这些 研究将通过与老鼠和人类的工作之间的持续对话进行：人类研究 使我们能够观察相关性，发展假设，并测试治疗策略；动物研究使 美国建立或驳斥微生物区系与宿主免疫学之间的因果关系，并获得 洞察力。这些数据将为临床试验的未来发展提供信息，以测试增强 接受CART和allo-HCT等癌症免疫治疗的患者的疗效和减毒作用。

ABSTRACT The gut microbiota consists of a community of diverse microbes and has many effects on human (patho)physiology. Microbiome composition has been associated with many diseases, but causal inference is often lacking. Preclinical and clinical studies have demonstrated that the intestinal microbiota can regulate innate and adaptive immunity, including T cell and antitumor immunity after allogeneic hematopoietic cell transplantation (allo-HCT) and checkpoint blockade. My lab has focused on the role of gut microbiota in outcomes of allo-HCT and immunotherapy. For example, we showed that microbiota composition undergoes significant and frequent changes during allo-HCT and that lower intestinal microbiota diversity is associated with increased mortality. We also found that dominance by certain species, most frequently Enterococcus, is associated with lethal graft-versus-host disease (GVHD); that exposure to certain antibiotics is associated with worse outcomes following allo-HCT and chimeric antigen receptor T cell (CART) therapy; and that hematopoietic reconstitution is associated with the presence of beneficial flora. These studies have been translated into clinical trials using autologous fecal microbiota transplant, administration of defined bacterial consortia, and antibiotic stewardship to spare and/or restore the commensal flora. The overarching hypothesis of this proposal is that the intestinal microbiome is an important modulator of innate and adaptive immunity in the setting of cancer immunotherapy. While immunotherapies are curative in some recipients, improving their efficacy and abating toxicities are unmet needs in oncology. The major goals are to improve cancer immunotherapy by targeting the intestinal microbiome based on preclinical and clinical studies. Examples of our ongoing and planned studies include: a) development of a new pipeline for microbiome analysis, b) preclinical and clinical projects regarding intestinal microbiome and CART, c) new techniques to analyze the effects of diet and drugs on the intestinal microbiome, and d) preclinical and clinical studies regarding immune modulation by bile acids, as an example how we study the mechanisms by which the intestinal microbiome can modulate immunity and cancer immunotherapy. We have organized a multicenter global consortium to collect fecal samples (funded separately from this application) along with a novel multi-omic approach to integrate patient, microbiome, and tumor profiling modalities using a computational platform (MSK-MIND) for data harmonization and machine learning. These investigations will be performed via perpetual dialogue between work with mice and humans: human studies enable us to observe correlations, develop hypotheses, and test therapeutic strategies; animal studies enable us to establish or refute causal relationships between microbiota and host immunology and to obtain mechanistic insights. These data will inform the future development of clinical trials to test therapeutic strategies to enhance efficacy and decrease toxicity in patients receiving cancer immunotherapy, such as CART and allo-HCT.