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Ferroptosis Characterization in Lung Adenocarcinomas Reveals Prognostic Signature With Immunotherapeutic Implication

ABSTRACT: The iron-dependent cell death named ferroptosis has been implicated in the progression and therapeutic response of several tumors. However, potential role of ferroptosis in lung adenocarcinomas (LUAD) remained less well understood. In TCGA-LUAD cohort, unsupervised clustering was first conducted based on ferroptosis regulators extracted from FerrDb database. Comprehensive correlation analysis and comparisons were performed among ferroptosis subtypes. The ferroptosis-related prognostic (FRP) signature was identified based on filtered features and repeated LASSO and was validated in five independent cohorts. The clinical relevance between the risk score and therapeutic response was further explored by multiple algorithms. qPCR was implemented to verify gene expression. A total of 1,168 LUAD patients and 161 ferroptosis regulators were included in this study. Three ferroptosis subtypes were identified and patients in subtype B had the best prognosis among the three subtypes. Significant differences in immune microenvironment and biological function enrichment were illustrated in distinct subtypes. The Boruta algorithm was conducted on 308 common differentially expressed genes for dimensionality reduction. A total of 56 genes served as input for model construction and a six-gene signature with the highest frequencies of 881 was chosen as FRP. The prognostic significance of FRP was validated in five independent cohorts. High FRP risk score was also linked to increased tumor mutation burden, PD-L1 protein expression and number of neoantigens. Of the FRP genes, 83.3% was abnormally expressed in LUAD cell lines. In conclusion, ferroptosis plays a non-negligible role in LUAD. Exploration of the ferroptosis pattern will enhance the prognostic stratification of individual patients and move toward the purpose of personalized treatment.

SUBMITTER: Sun S

PROVIDER: S-EPMC8563998 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: We aimed to investigate the immunological significance of M2 macrophage-related genes in lung cancer (LC) patients, specifically focusing on constructing a risk score to predict patient prognosis and response to immunotherapy. Methods: We developed a novel risk score by identifying and incorporating 12 M2 macrophage-related genes. The risk score was calculated by multiplying the expression levels of risk genes by their respective coefficients. Through comprehensive enrichment analysis, we explored the potential functions distinguishing high- and low-risk groups. Moreover, we examined the relationship between patients in different risk groups and immune infiltration as well as their response to immunotherapy. The single-cell RNA sequencing data were acquired to ascertain the spatial pattern of RNF130 expression. The expression of RNF130 was examined using TCGA datasets and verified by HPA. The qRT-PCR was employed to examine RNF130 expression in LC cells. Finally, in vitro experiments were carried out to validate the expression and function of RNF130. Results: Our results indicated that the risk score constructed from 12 M2 macrophage-related genes was an independent prognostic factor. Patients in the high-risk group had a significantly worse prognosis compared to those in the low-risk group. Functional enrichment analysis showed a significant relationship between the risk score and immunity. Furthermore, we explored immune infiltration in different risk groups using seven immune algorithms. The results demonstrated a negative correlation between high-risk group patients and immune infiltration of B cells, CD4+ cells, and CD8+ cells. We further validated these findings using an immunotherapy response database, which revealed that high-risk patients were more likely to exhibit immune evasion and might have poorer immunotherapy outcomes. Additionally, drug sensitivity analysis indicated that patients in the high-risk group were more sensitive to certain chemotherapeutic and targeted drugs than those in the low-risk group. Single-cell analysis indicated that macrophages were the primary site of RNF130 distribution. The results from the TCGA and HPA database demonstrated a trend toward a low expression of RNF130 in LC. Finally, in vitro experiments further validated the expression and function of RNF130 in LC cells. Conclusions: The high-risk group constructed with M2 macrophage-related genes in LC was closely associated with poor prognosis, low immune cell infiltration, and poorer response to immunotherapy. This risk score can help differentiate and predict the prognosis and immune status of LC patients, thereby aiding in the development of precise and personalized immunotherapy strategies.

Project description:BackgroundLung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer. Ferroptosis is a newly recognized process of cell death, which is different from other forms of cell death in morphology, biochemistry, and genetics, and has played a vital role in cancer biology. This study aimed to identify a ferroptosis-related gene signature associated with LUAD prognosis.MethodsDataset TCGA-LUAD which came from the TCGA portal was taken as the training cohort. GSE72094 and GSE68465 from the GEO database were treated as validation cohorts. Two hundred fifty-nine ferroptosis-related genes were retrieved from the FerrDb database. In the training cohort, Kaplan-Meier and univariate Cox analyses were conducted for preliminary screening of ferroptosis-related genes with potential prognostic capacity. These genes then entered into the LASSO Cox regression model, constructing a gene signature. The latter was then evaluated in the training and validation cohorts via Kaplan-Meier, Cox, and ROC analyses. In addition, the correlations between risk score and autophagy were examined by Pearson correlation coefficient. The analyses of GSEA and immune infiltrating were performed for better studying the function annotation of the gene signature and the character of each kind of immune cells played in the tumor microenvironment.ResultsA 15-gene signature was found from the training cohort and validated by Kaplan-Meier and Cox regression analyses, revealing its independent prognosis value in LUAD. Moreover, the ROC analysis was conducted, confirming a strong predictive ability that this signature owned for LUAD prognosis. One hundred fifty-one of 222 (68.01%) autophagy-related genes were discovered significantly correlated with risk scores. Analyses of GSEA and immune infiltration exhibited in detail the specific pathways that associate with the 15-gene signature and identified the crucial roles of resting mast cells and resting dendritic cells owned in the prognosis of the 15-gene signature.ConclusionIn this present study, a novel ferroptosis-related 15-gene signature (RELA, ACSL3, YWHAE, EIF2S1, CISD1, DDIT4, RRM2, PANX1, TLR4, ARNTL, LPIN1, HERPUD1, NCOA4, PEBP1, and GLS2) was built. It could accurately predict the prognosis of LUAD and was related to resting mast cells and resting dendritic cells, which provide potential for the personalized outcome prediction and the development of new therapies in LUAD population.

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Ferroptosis Characterization in Lung Adenocarcinomas Reveals Prognostic Signature With Immunotherapeutic Implication

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