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Research on Differences and Immune Infiltration-Related Macrophages Between Non-Small Cell Lung Cancer and Adjacent Tissues

ABSTRACT: Non-Small Cell Lung Cancer (NSCLC) is a highly lethal respiratory tumor with unclear molecular mechanisms. RNA-seq data from 34 early-stage samples and adjacent non-cancerous tissues identified 1088 differentially expressed genes using Deseq2. Mendelian randomization (MR) analysis of 26,153 genes and 63,053 LUSC patients, including 7,838,805 SNPs, identified 213 potential exposure factors. Five differentially expressed genes (GYPE, PODXL2, RNF182, SIRPG, WNT7A) were identified, with PODXL2 as a risk factor. GO and KEGG analyses highlighted the mTOR and Wnt signaling pathways. Immune infiltration analysis showed decreased Plasma cells, Tregs, and activated Dendritic cells, but increased Macrophages M1. External validation using TCGA and 11 GEO datasets confirmed SIRPG's role in LUSC. SIRPG is a significant exposure risk factor for LUSC, with Macrophages M1 and the mTOR signaling pathway playing crucial roles.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268175 | GEO | 2024/05/29

REPOSITORIES: GEO

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Project description:Background: When exposed to specific stimuli, macrophages exhibit distinct activation programs, M1 and M2 polarization, that define macrophage function as inflammatory/immune effectors or anti-inflammatory/tissue remodeling cells, respectively. Due to their position on the lung epithelial surface, alveolar macrophages (AM) directly interact with environmental stimuli such as cigarette smoke, the major risk factor for the development of chronic obstructive pulmonary disease (COPD). Based on the current paradigm that, in response to smoking, AM contribute to both inflammatory and tissue remodeling processes in the lung relevant to the pathogenesis of COPD, we hypothesized that chronic exposure to cigarette smoking activates both the M1 and M2 polarization programs in AM. Methods and Findings: To assess this hypothesis, global transcriptional profiling with TaqMan confirmation and flow cytometry analysis was carried out on AM obtained by bronchoalveolar lavage of 24 healthy nonsmokers, 34 healthy smokers and 12 smokers with COPD to assess the expression of 41 M1 genes and 32 M2 genes in each group. Contrary to our expectations, while there was up-regulation of some genes typical for M2-related phenotypes, AM of healthy smokers exhibited substantial suppression of M1-related inflammatory/immune genes. These M1- and M2-related changes progressed with the development of smoking-induced lung disease, with AM of smokers with COPD exhibiting further down-regulation of M1-related genes accompanied with further up-regulation of some M2-related genes. Conclusion: The data demonstrates that the modifications of the AM transcriptome associated with smoking result in a unique phenotype characterized by reprogramming of AM towards M1-deactivated partially M2-polarized macrophages and suggests that, while AM likely contribute to smoking-induced tissue remodeling, the role of AM in the early pathogenesis of smoking-induced COPD in humans is not inflammatory. This concept is a departure from the conventional concept that AM-mediated inflammation participates in the early derangements of the lung induced by smoking, and suggests a novel paradigm for conceptualizing COPD and developing new approaches to prevent the development of smoking-induced lung disease. Comparison of gene expression in alveolar macrophages of normal non-smokers and normal smokers and smokers with COPD

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Research on Differences and Immune Infiltration-Related Macrophages Between Non-Small Cell Lung Cancer and Adjacent Tissues

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