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 微环境（TME）是其发展的基础。尽管微生物群和免疫细胞都发挥着重要作用， 在TME中，将特定的肺部微生物群变化与免疫细胞联系起来存在巨大差距， 亚群到目前为止，还没有人肺癌研究已经进行了表征宿主病原体 动态变化，并以综合方式剖析微生物组-免疫相互作用。 我们假设，肺部驻留微生物的生态失调（微生物群表达变化）触发了 肺免疫系统的平衡失调（免疫细胞浸润水平），导致 炎症性TME，并进一步促进肺肿瘤发生和肿瘤进展。我们建议利用 在来自200名早期（I-IIIA）肺腺癌患者的现有RNA-Seq（肿瘤和邻近组织）上， 来自贝勒医学院（Baylor College of Medicine）研究（discovery，n = 100）和哈佛公共卫生学院研究 （外部验证，n = 100），该应用程序没有成本。我们的目标是揭示肺的影响 微生物群对宿主免疫细胞谱的影响以及它们的相互作用如何有助于肿瘤发生和肿瘤 进展为了实现我们的目标，我们将利用双重RNA-Seq分析方法：1）鉴定 肿瘤内元转录组学特征，和2）表征免疫浸润概况和微生物组- 免疫相互作用具体而言，未映射的质量过滤的RNA读数（非人类，推定的微生物读数） 与微生物参考转录组比对的读数将用于元转录组分析（Aim 1）; 该映射到人参考将用于计算免疫谱分析（Aim 2）。 这是第一项同时分析肺组织特异性微生物群表达和免疫浸润的研究。 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。 肺腺癌发展之前/期间（邻近/肿瘤组织）的过程，特别是复杂的 微生物组-免疫相互作用。阐明肺部微生物组与免疫系统之间相互作用的性质 包含TME的细胞可以指导新的治疗干预的开发。

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.