Evaluating Etiological Impact of Metatranscriptomic and Immunological Features for Lung Cancer

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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.