AUTHOR=Li Zhaoxun , Zhou Bin , Zhu Xinsheng , Yang Fujun , Jin Kaiqi , Dai Jie , Zhu Yuming , Song Xiao , Jiang Gening 

TITLE=Differentiation-related genes in tumor-associated macrophages as potential prognostic biomarkers in non-small cell lung cancer

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1123840

DOI=10.3389/fimmu.2023.1123840

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>The purpose of this study was to evaluate the role of differentiation-related genes (DRGs) in tumor-associated macrophages (TAMs) in non-small cell lung cancer (NSCLC).</p></sec><sec><title>Methods</title><p>Single cell RNA-seq (scRNA-seq) data from GEO and bulk RNA-seq data from TCGA were analyzed to identify DRGs using trajectory method. Functional gene analysis was carried out by GO/KEGG enrichment analysis. The mRNA and protein expression in human tissue were analyzed by HPA and GEPIA databases. To investigate the prognostic value of these genes, three risk score (RS) models in different pathological types of NSCLC were generated and predicted NSCLC prognosis in datasets from TCGA, UCSC and GEO databases.</p></sec><sec><title>Results</title><p>1,738 DRGs were identified through trajectory analysis. GO/KEGG analysis showed that these genes were predominantly related to myeloid leukocyte activation and leukocyte migration. 13 DRGs (<italic>C1QB, CCL4, CD14, CD84, FGL2, MS4A6A, NLRP3, PLEK, RNASE6, SAMSN1, SPN, TMEM176B, ZEB2</italic>) related to prognosis were obtained through univariate Cox analysis and Lasso regression. <italic>C1QB</italic>, <italic>CD84</italic>, <italic>FGL2</italic>, <italic>MS4A6A</italic>, <italic>NLRP3</italic>, <italic>PLEK</italic>, <italic>SAMSN1</italic>, <italic>SPN</italic>, and <italic>ZEB2</italic> were downregulated in NSCLC compared to non-cancer tissue. The mRNA of 13 genes were significantly expressed in pulmonary macrophages with strong cell specificity. Meanwhile, immunohistochemical staining showed that <italic>C1QB, CCL4, SPN, CD14, NLRP3, SAMSN1, MS4A6A, TMEM176B</italic> were expressed in different degrees in lung cancer tissues. <italic>ZEB2</italic> (HR=1.4, P&lt;0.05) and <italic>CD14</italic> (HR=1.6, P&lt;0.05) expression were associated with a worse prognosis in lung squamous cell carcinoma; <italic>ZEB2</italic> (HR=0.64, P&lt;0.05), <italic>CD84</italic> (HR=0.65, P&lt;0.05), <italic>PLEK</italic> (HR=0.71, P&lt;0.05) and <italic>FGL2</italic> (HR=0.61, P&lt;0.05) expression were associated with a better prognosis in lung adenocarcinoma. Three RS models based on 13 DRGs both showed that the high RS was significantly associated with poor prognosis in different pathological types of NSCLC.</p></sec><sec><title>Conclusions</title><p>This study highlights the prognostic value of DRGs in TAMs in NSCLC patients, providing novel insights for the development of therapeutic and prognostic targets based on TAM functional differences.</p></sec>