Evaluating Etiological Impact of Metatranscriptomic and Immunological Features for Lung Cancer

摘要 越来越多的证据表明，癌症的演变强烈依赖于复杂的肿瘤。 发育的微环境(TME)。尽管微生物群和免疫细胞都扮演着重要的角色 在TME内部，在将特定的肺部微生物区系变化与免疫细胞联系起来方面存在巨大的差距 亚群。到目前为止，还没有进行人类肺癌的研究来确定宿主病原体的特征。 微生物-免疫相互作用的动态变化和综合剖析。 我们假设，肺部微生物的失调(微生物区系表达的变化)触发了 肺免疫系统的失衡平衡(免疫细胞渗透水平)，导致 炎性TME，并进一步促进肺肿瘤的发生和肿瘤的进展。我们打算利用这笔钱 在200例早期(I-IIIA)肺腺癌患者的现有RNA-Seq(肿瘤及邻近组织)上， 来自贝勒医学院(BCM)的一项研究(发现，n=100)和哈佛大学公共卫生学院的一项研究 (外部验证，n=100)，此应用程序不承担任何费用。我们的目标是揭示肺的影响 宿主免疫细胞的微生物区系及其相互作用在肿瘤发生和肿瘤中的作用 进步。为了实现我们的目标，我们将利用双重RNA-Seq分析方法：1)识别 肿瘤内的转录本特征，以及2)表征免疫浸润谱和微生物组-- 免疫相互作用。具体地说，未映射的经过质量过滤的RNA读取(非人类的、假定的微生物读取) 将使用与微生物参考转录本相匹配的转录组分析(目标1)； 这种与人类参照的映射将被用于计算免疫图谱分析(目标2)。 这是第一个同时分析肺组织特定微生物区系表达和免疫浸润物的研究 在肺腺癌中。这个项目可以大大有助于我们对生物学的理解 在(邻近/肿瘤组织)肺腺癌发展之前/期间的过程，特别是复合体 微生物-免疫相互作用。阐明肺微生物群与免疫相互作用的本质 组成TME的细胞可以指导新的治疗干预措施的开发。

ABSTRACT There is increasing evidence that the evolution of cancer is strongly dependent on the complex tumor microenvironment (TME) in which it develops. Despite the important roles of both microbiota and immune cells within TME, there are huge gaps in linking specific lung-residing microbiota changes with immune cell subpopulations. To date, no human lung cancer studies have been performed to characterize the host-pathogen dynamic changes and dissecting the microbiome-immune interaction in an integrated manner. We hypothesize that the dysbiosis of lung-residing microbe (microbiota expression changes) triggers dysregulated balance in the lung immune system (immune cells infiltration levels), which results in an inflammatory TME, and further promotes lung tumorigenesis and tumor progression. We propose to capitalize on existing RNA-Seq (tumor and adjacent tissue) from 200 early-stage (I–IIIA) lung adenocarcinoma patients, from a Baylor College of Medicine (BCM) study (discovery, n = 100) and a Harvard School of Public Health study (external validation, n = 100), with no cost to this application. Our goal is to reveal the impact of the lung microbiota on host immune cell profiles and how their interaction contributes to tumorigenesis and tumor progression. To accomplish our goals, we will utilize a Dual RNA-Seq analytical approach: 1) to identity intratumoral metatranscriptomic signatures, and 2) to characterize immune infiltration profiles and microbiome- immune interaction. Specifically, the unmapped quality-filtered RNA reads (non-human, putative microbial reads) aligned to microbial reference transcriptomes will be used for metatranscriptome analysis (Aim 1); whereas reads that map to human reference will be used for computational immune profiling analysis (Aim 2). This is the first study to simultaneously profile lung tissue-specific microbiota expression and immune infiltrates in lung adenocarcinoma. This project could contribute significantly to our understanding of the biological processes before/during (adjacent/tumor tissue) lung adenocarcinoma development, in particular the complex microbiome-immune interaction. Elucidating the nature of interactions between lung microbiome and immune cells comprising the TME could guide the development of novel therapeutic interventions.