A prospective evaluation of the gut microbiome as a mediator of lymphoma treatment outcome and systemic immunity

摘要/摘要 弥漫性大B细胞淋巴瘤(DLBCL)是最常见的淋巴瘤，是一种重要的临床问题，只有 60%的患者治愈。免疫癌症DLBCL如何逃避宿主防御的机制很差 明白了。越来越多的证据表明，人类肠道微生物区系(GMB)在调节 先天免疫和获得性免疫，并与多种实体肿瘤的治疗结果相关。基座 在这一点上，我们假设GMB通过改变抗肿瘤来影响淋巴瘤的行为 免疫反应。我们的初步数据提供了令人信服的证据，表明DLBCL患者：a)有明显的 GMB组成，其中许多共生家庭丢失；以及b)在中央和 效应器记忆T细胞。然而，GMB和淋巴瘤之间的联系仍然知之甚少。 限制靶向治疗的发展。拟议研究的总体目标是调查 纵向研究GMB信号对DLBCL临床反应和系统免疫的影响。 因此，我们的具体目标是：目标1：在未经治疗的DLBCL中调查GMB与 应用16S和全基因组鸟枪法测定300例患者粪便标本的疗效 治疗前、治疗中和治疗12个月时，临床结果的有效终点；目标2：评估 通过追踪并发大便和每周血液，GMB和DLBCL之间潜在的双向关联 我们将用新的贝叶斯时间序列方法分析每天50名DLBCL患者的样本 在治疗的前14天，然后在目标1的随访中；目标3：调查功能 免疫激活与微生物多样性之间的关系，包括微生物产品的转运 从肠道进入血液并扩增抗原特异性T细胞，直接对抗不良结果的微生物。 这一科学前提得到了广泛的试点数据和既定方法的严格应用的支持。 拟议的研究具有很高的创新性，因为它将是第一个大规模的纵向和前瞻性研究 用全基因组猎枪等最先进的方法研究淋巴瘤中的GMB 测序、AbSeq和贝叶斯时间序列分析。这项研究具有显著进步的潜力 通过确定影响治疗失败的GMB和系统免疫途径进行淋巴瘤研究 DLBCL，可能为新的个体化治疗提供生物学见解。我们将在我们的调查结果的基础上 开发个性化的基于微生物的疗法，范围可能从有利于 我们证明有益的生物体的生长，对靶向益生菌治疗和/或粪便移植有利 我们展示的减少微生物是有害的。因为肠道细菌是可以改变的，我们的发现可能会导致 一种新的、毒性最小的治疗范例--量身定制的微生物疗法的实施前景 对于DLBCL患者来说，这是一个重要的未得到满足的医疗需求。

ABSTRACT/SUMMARY Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, is a significant clinical problem, with only 60% of patients cured. Mechanisms for how DLBCL, an immune cancer, evades host defenses are poorly understood. Growing evidence suggests that the human gut microbiota (GMB) plays important roles in regulating innate and adaptive immunity, and is associated with therapeutic outcome in multiple solid tumor types. Based on this connection, we hypothesize that the GMB influences lymphoma behavior by altering the anti-tumor immune response. Our preliminary data provide compelling evidence that DLBCL patients: a) have distinct GMB compositions in which many commensal families are lost; and b) show chronic activation in central and effector memory T cells. However, the connections between GMB and lymphoma remain poorly understood, limiting the development of targeted therapies. The overall goal of the proposed research is to investigate longitudinally the impact of GMB signatures on clinical response and systemic immunity in DLBCL. Thus, our specific aims are: Aim 1: To investigate in untreated DLBCL the association between the GMB and treatment response using 16S and full metagenomic shotgun sequencing of stool samples from 300 patients pre-treatment, during treatment, and at 12 months, a validated endpoint for clinical outcome; Aim 2: To evaluate the potential bi-directional associations between GMB and DLBCL by tracking concurrent stool and weekly blood samples which we will analyze with novel Bayesian timeseries methods for a subset of 50 DLBCL patients daily during the first 14 days of treatment, and then in follow-up as in Aim 1; Aim 3: To investigate functional relationships between immune activation and microbial diversity, including translocation of microbial products from the gut into the blood and expansion of antigen-specific T cells directed against poor outcome microbes. The scientific premise is supported by extensive pilot data and rigorous application of established methods. The proposed study is highly innovative, as it will be the first large scale longitudinal and prospective investigation of the GMB in lymphoma, using state of the art methodologies such as, full metagenomic shotgun sequencing, AbSeq, and Bayesian time series analysis. This research has the potential to significantly advance lymphoma research by identifying the GMB and systemic immune pathways that impact treatment failure in DLBCL, and it may provide the biologic insights for new personalized therapeutics. We will build on our findings to develop personalized microbial-based therapies, which could range from dietary changes that would favor growth of organisms we demonstrate to be beneficial, to targeted probiotic therapy and/or fecal transplantation to reduce microbes we show are deleterious. Because gut bacteria are modifiable, our findings could lead in the future to the implementation of tailored microbial-based therapies, a new and minimally toxic treatment paradigm for DLBCL patients, a significant unmet medical need.