A Novel Immune-Related Prognostic Model for Response to Immunotherapy and Survival in Patients With Lung Adenocarcinoma.
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ABSTRACT:
SUBMITTER: Zheng Y
PROVIDER: S-EPMC8017122 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Lung adenocarcinoma (LUAD) is the major subtype of lung cancer and has a poor prognosis. Disulfidptosis is a novel regulated cell death form characterized by aberrant disulfide stress and actin network collapse. This study aimed to identify disulfidptosis-related lncRNAs, and predict LUAD patients' prognosis and response to antitumor therapies by establishing a disulfidptosis-related lncRNA model. Methods: Transcriptome and clinical data of LUAD patients were obtained from the TCGA database. Pearson correlation and Cox regression analysis was used to identify disulfidptosis-related lncRNAs associated with overall survival. LASSO regression analysis was adopted to construct the prognostic model. GO, KEGG and GSEA analysis was used to identify cellular pathways related to this model. Immune cell infiltration was investigated by ESTIMATE and CIBERSORT algorithms. Tumor mutational burden (TMB) and its association with model-derived risk score were analyzed using simple nucleotide variation data. Patients' response to immunotherapy and other antineoplastic drugs was predicted by the TIDE algorithm and GDSC tool, respectively. Results: We identified 127 disulfidptosis-related lncRNAs, and a prognostic model that consists eight of them (KTN1-AS1, AL365181.3, MANCR, LINC01352, AC090559.1, AC093673.1, AP001094.3, and MHENCR) was established and verified. The prognostic model could stratify LUAD patients into two distinct risk-score groups. A high risk score was an independent prognosis factor indicating poor overall survival, and correlated with reduced immune cell infiltration, high TMB, and lower activity of tumor immune response. Immune checkpoint blockade might bring more survival benefits to the high-risk LUAD patients, whereas low-risk patients might be more responsive to targeted therapy and diverse kinase inhibitors. Conclusion: We established a disulfidptosis-related lncRNA model that can be exploited to predict the prognosis, tumor mutational burden, immune cell infiltration landscape, and response to immunotherapy and targeted therapy in LUAD patients.
| S-EPMC10563764 | biostudies-literature
Project description:We searched for a predictive biomarker that also predicts whether patients would benefit from immune checkpoint blockade (ICB) treatment from a few angles, because existing biomarkers no longer wholly replicate the interconnections of distinctive elements in the tumor microenvironment (TME). We identified 55 pivotal IRGs by performing a WGCNA and univariate Cox regression analysis on a lung adenocarcinoma dataset from the TCGA database. The IRGPI model was then constructed using multivariate Cox regression analysis, which identified 16 genes and verified the use of the GSE68465 database. The AUC of the IRGPI was compared to those of the current biomarkers to determine its predictive potential. Then we examined the molecular and immunological properties of ICB and assessed its effectiveness using CTLA4 expression and TIDE. Patients with a high IRGPI had a later clinical stage, more severe symptoms, and a worse prognosis. Patients with a low IRGPI had a higher immune escape potential and were less responsive to immunotherapy. The IRGPI may be a biomarker for determining the prognosis of patients and whether they respond favorably to ICB therapy.
| S-EPMC10641371 | biostudies-literature
Project description:BackgroundThe tumor microenvironment plays an important role in the progression and malignancy of lung adenocarcinoma and affects the immunotherapy response. There is increasing evidence that long non-coding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs) have significant functions in the development and treatment response of various kinds of cancer. This study aimed to explore the association between immune-related lncRNA-microRNA (miRNA)-messenger RNA (mRNA)-ceRNA networks, and the prognosis of and immunotherapy response in lung adenocarcinoma.MethodsRNA-sequencing (RNA-seq) and miRNA-seq data from The Cancer Genome Atlas (TCGA) were used to evaluate the infiltration of immune cells in lung adenocarcinoma samples by undertaking a single-sample gene set enrichment analysis (ssGSEA) to divide the cells into high and low immune cell infiltration groups. The differentially expressed mRNA (DEmRNA) was further analyzed by a weighted gene co-expression network analysis (WGCNA), search tool for recurring instances of neighboring genes (STRING), and Cytoscape to select hub genes. The ceRNA network was constructed using Cytoscape. Additionally, survival analyses were conducted to screen out prognostic candidate genes.ResultsSeven thousand five hundred and thirty-eight mRNAs, 540 lncRNAs, and 138 miRNAs were found to be differentially expressed between the high and low immune cell infiltration groups. The two DEmRNA modules most significantly associated with immune cell infiltration were further analyzed, and four clusters, including 179 DEmRNAs, were selected based on Molecular Complex Detection (MCODE) scores. The selected DEmRNAs in the four clusters were mainly enriched in pathways involved in regulating the immune response. Ultimately, a ceRNA network of SNHG6-hsa-miR-30e-5p-CYSLTR1 was identified as being associated with the prognosis of and immunotherapy response in lung adenocarcinoma.ConclusionsThe present study extends understandings of immune-related lncRNA-miRNA-mRNA-ceRNA networks and identifies novel targets and a regulatory pathway for anti-tumor immunotherapy.
| S-EPMC8506752 | biostudies-literature
Project description:Lung adenocarcinoma accounts for the majority of lung cancer cases and impact survival rate of patients severely. Immunotherapy is an effective treatment for lung adenocarcinoma but is restricted by many factors including immune checkpoint expression and the inhibitory immune microenvironment. This study aimed to explore the immune microenvironment in lung adenocarcinoma via disulfidptosis. Public datasets of lung adenocarcinoma from the TCGA and GEO was adopted as the training and validation cohort. Based on the differences in the expression of disulfidptosis -related genes, a glucose metabolism and immune response prognostic model was constructed. The prognostic value and clinical relationship of the model were further explored. Immune-related analyses were performed according to CIBERSORT, ssGSEA, TIDE, IPS. We verified that the model could accurately predict the survival expectancy of lung adenocarcinoma patients. Patients with lung adenocarcinoma and a low-risk score had better survival outcomes according to the model. Moreover, the high-risk group tended to have an immunosuppressive effect, as reflected by the immune cell components, phenotypes and functions. We also found that the clinically relevant immune checkpoint CTLA-4 was significantly higher in low-risk group (P<0.05), indicating that the high-risk group may suffer worse tumor immunotherapy efficacy. Finally, we found that this model has accurate predictive value for the efficacy of immune checkpoint blockade in non-small cell lung cancer (P<0.05). The prognostic model demonstrated the feasibility of predicting survival and immunotherapy efficacy via disulfidptosis-related genes and will facilitate the development of personalized anticancer therapy.
| S-EPMC11291233 | biostudies-literature
Project description:Lung cancer is one of the most common malignant tumors, and ranks high in the list of mortality due to cancers. Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Despite progress in the diagnosis and treatment of lung cancer, the prognosis of these patients remains dismal. Therefore, it is crucial to identify the predictors and treatment targets of lung cancer to provide appropriate treatments and improve patient prognosis. In this study, the gene modules related to immunotherapy were screened by weighted gene co-expression network analysis (WGCNA). Using unsupervised clustering, patients in The Cancer Genome Atlas (TCGA) were divided into three clusters based on the gene expression. Next, gene clustering was performed on the prognosis-related differential genes, and a six-gene prognosis model (comprising PLK1, HMMR, ANLN, SLC2A1, SFTPB, and CYP4B1) was constructed using least absolute shrinkage and selection operator (LASSO) analysis. Patients with LUAD were divided into two groups: high-risk and low-risk. Significant differences were found in the survival, immune cell infiltration, Tumor mutational burden (TMB), immune checkpoints, and immune microenvironment between the high- and low-risk groups. Finally, the accuracy of the prognostic model was verified in the Gene Expression Omnibus (GEO) dataset in patients with LUAD (GSE30219, GSE31210, GSE50081, GSE72094).
| S-EPMC9772350 | biostudies-literature
Project description:ObjectFocus on immune-related gene pairs (IRGPs) and develop a prognostic model to predict the prognosis of patients with lung adenocarcinoma (LUAD).MethodsFirst, the LUAD patient dataset was downloaded from The Cancer Genome Atlas database, and paired analysis of immune-related genes was subsequently conducted. Then, LASSO regression was used to screen prognostic IRGPs for building a risk prediction model. Meanwhile, the Gene Expression Omnibus database was used for external validation of the model. Next, the clinical predictive power of IRGPs features was assessed by uni-multivariate Cox regression analysis, the infiltration of key immune cells in high and low IRGPs risk groups was analyzed with CIBERSORT, quanTIseq, and Timer, and the key pathways enriched for IRGPs were assessed using the Kyoto Encyclopedia of Genes and Genomes. Finally, the expression and related functions of key immune cells and genes were verified by immunofluorescence and cell experiments of tissue samples.ResultsIt was revealed that the risk score of 19 IRGPs could be used as accurate indicators to evaluate the prognosis of LUAD patients, and the risk score was mainly related to T cell infiltration based on CIBERSORT analysis. Two genes of IRGPs, IL6, and CCL2, were found to be closely associated with the expression of PD-1/PD-L1 and the function of T-cells. Depending on the results of tissue immunofluorescence, IL6, CCL2, and T cells were highly expressed in the LUAD tissues of patients. Furthermore, IL6 and CCL2 were positively correlated with the expression of T cells. Besides, qRT-PCR assay in four different LUAD cells proved that IL6 and CCL2 were positively correlated with the expression of PD-L1 (P < .001).ConclusionsBased on 19 IRGPs, an effective prognosis model was established to predict the prognosis of LUAD patients. In addition, IL6 and CCL2 are closely related to the function of T-cells.
| S-EPMC9834935 | biostudies-literature
Project description:BackgroundClinically, only a minority of patients benefit from immunotherapy and few efficient biomarkers have been identified to distinguish patients who would respond to immunotherapy. The tumor microenvironment (TME) is reported to contribute to immunotherapy response, but details remain unknown. We aimed to construct a prognostic model based on the TME of lung adenocarcinoma (LUAD) to predict the prognosis and immunotherapy efficacy.MethodsWe integrated computational algorithms to describe the immune infiltrative landscape of LUAD patients. With the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses, we developed a LUAD tumor microenvironment prognostic signature (LATPS). Subsequently, the immune characteristics and the benefit of immunotherapy in LATPS-defined subgroups were analyzed. RNA sequencing of tumor samples from 28 lung cancer patients treated with anti-PD-1 therapy was conducted to verify the predictive value of the LATPS.ResultsWe constructed the LATPS grounded on four genes, including UBE2T, KRT6A, IRX2, and CD3D. The LATPS-low subgroup had a better overall survival (OS) and tended to have a hot immune phenotype, which was characterized by an elevated abundance of immune cell infiltration and increased activity of immune-related pathways. Additionally, tumor immune dysfunction and exclusion (TIDE) score was markedly decreased in the LATPS-low subgroup, indicating an enhanced opportunity to benefit from immunotherapy. Survival analysis in 28 advanced lung cancer patients treated with an anti-PD-1 regimen at Nanfang hospital revealed that the LATPS-low subgroup had better immunotherapy benefit.ConclusionLATPS is an effective predictor to distinguish survival, immune characteristics, and immunotherapy benefit in LUAD patients.
| S-EPMC9729252 | biostudies-literature
Project description:BackgroundThere is increasing evidence of the effectiveness of immune checkpoint blockade (ICB) therapy for the treatment of lung adenocarcinoma (LUAD). However, the benefits of ICB therapy vary among LUAD patients. Due to the research dimension, existing biomarkers, such as programmed death-ligand 1 (PD-L1) expression and tumor mutation burden (TMB), could not reflect the complex tumor environment, and had low prediction accuracy of ICB. Therefore, we aimed to uncover a prognostic biomarker that could also predict whether a patient would benefit from ICB therapy and other common treatments from multiple dimensions, so as to improve the prediction accuracy of pre-treatment patients.MethodsBased on the LUAD dataset retrieved from The Cancer Genome Atlas (TCGA) database, 50 immune-related hub genes were identified using weighted gene co-expression network analysis and univariate Cox regression analyses. An immune-related gene prognostic index (IRGPI) was constructed using a Cox proportional-hazards model based on 15 genes and validated using GSE72094 dataset. We tested its prognostic accuracy by Kaplan-Meier (K-M) survival curves of the two datasets and assessed its predictive power by comparing area under curve (AUC) of IRGPI with existing biomarkers. Subsequently, we analyzed the molecular and immune characteristics, and evaluated the benefits of ICB by PD-L1 expression and Tumor Immune Dysfunction and Exclusion (TIDE) analysis, predicted the inhibitory concentration 50 of common treatments drugs for two IRGPI score-related subgroups.ResultsPatients in the IRGPI-high subgroup had lower overall survival (OS) than patients in the IRGPI-low subgroup in K-M survival curve in two cohorts. And IRGPI has AUC values of 0.715, 0.724, and 0.743 in 1, 2, and 3 years, respectively. A higher tumor mutation burden and PD-L1 expression and the tumor microenvironment (TME) landscape demonstrated that IRGPI-high subgroup patients may respond better to ICB therapy. Genomics of Drug Sensitivity in Cancer (GDSC) analysis indicated that the IRGPI-high subgroup showed greater sensitivity to chemotherapy.ConclusionsIRGPI is a prospective biomarker for evaluating whether a patient will benefit from ICB therapy and other treatments, and distinguishing patients with different molecular and immune characteristics.
| S-EPMC9264088 | biostudies-literature
Project description:PURPOSE:We combined conventional clinical and pathological characteristics and pathological architectural grading scores to develop a prognostic model to identify a specific group of patients with stage I lung adenocarcinomas with poor survival following surgery. METHODS:This retrospective study included 198 patients with stage I lung adenocarcinomas recruited from 2004 to 2013. Multivariate analyses were used to confirm independent risk factors, which were checked for internal validity using the bootstrapping method. The prognostic scores, derived from β-coefficients using the Cox regression model, classified patients into high- and low-risk groups. The predictive performance and discriminative ability of the model were assessed by the area under the receiver operating characteristic curve (AUC), concordance index (C-index) and Kaplan-Meier survival analyses. RESULTS:Three risk factors were identified: T2 (rounding of β-coefficients = 81), necrosis (rounding of β-coefficients = 67), and pathological architectural score of 5-6 (rounding of β-coefficients = 58). The final prognostic score was the sum of points. The derived prognostic scores stratified patients into low- (score ≤ 103) and high- (score > 103) risk groups, with significant differences in 5-year overall survival (high vs. low risk: 49.3% vs. 88.0%, respectively; hazard ratio: 4.55; p < 0.001). The AUC for the proposed model was 0.717. The C-index of the model was 0.693. CONCLUSION:An integrated prognostic model was developed to discriminate resected stage I adenocarcinoma patients into low- and high-risk groups, which will help clinicians select individual treatment strategies.
| S-EPMC7040084 | biostudies-literature
Project description:BackgroundLung adenocarcinoma (LUAD) originates mainly from the mucous epithelium and glandular epithelium of the bronchi. It is the most common pathologic subtype of non-small cell lung cancer (NSCLC). At present, there is still a lack of clear criteria to predict the efficacy of immunotherapy. The 5-year survival rate for LUAD patients remains low.MethodsAll data were downloaded from The Cancer Genome Atlas (TCGA) database. We used Gene Set Enrichment Analysis (GSEA) database to obtain immune-related mRNAs. Immune-related lncRNAs were acquired by using the correlation test of the immune-related genes with R version 3.6.3 (Pearson correlation coefficient cor = 0.5, P < 0.05). The TCGA-LUAD dataset was divided into the testing set and the training set randomly. Based on the training set to perform univariate and multivariate Cox regression analyses, we screened prognostic immune-related lncRNAs and given a risk score to each sample. Samples were divided into the high-risk group and the low-risk group according to the median risk score. By the combination of Kaplan-Meier (KM) survival curve, the receiver operating characteristic (ROC) (AUC) curve, the independent risk factor analysis, and the clinical data of the samples, we assessed the accuracy of the risk model. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on the differentially expressed mRNAs between the high-risk group and the low-risk group. The differentially expressed genes related to immune response between two risk groups were analyzed to evaluate the role of the model in predicting the efficacy and effects of immunotherapy. In order to explain the internal mechanism of the risk model in predicting the efficacy of immunotherapy, we analyzed the differentially expressed genes related to epithelial-mesenchymal transition (EMT) between two risk groups. We extracted RNA from normal bronchial epithelial cell and LUAD cells and verified the expression level of lncRNAs in the risk model by a quantitative real-time polymerase chain reaction (qRT-PCR) test. We compared our risk model with other published prognostic signatures with data from an independent cohort. We transfected LUAD cell with siRNA-LINC0253. Western blot analysis was performed to observed change of EMT-related marker in protein level.ResultsThrough univariate Cox regression analysis, 24 immune-related lncRNAs were found to be strongly associated with the survival of the TCGA-LUAD dataset. Utilizing multivariate Cox regression analysis, 10 lncRNAs were selected to establish the risk model. The K-M survival curves and the ROC (AUC) curves proved that the risk model has a fine predictive effect. The GO enrichment analysis indicated that the effect of the differentially expressed genes between high-risk and low-risk groups is mainly involved in immune response and intercellular interaction. The KEGG enrichment analysis indicated that the differentially expressed genes between high-risk and low-risk groups are mainly involved in endocytosis and the MAPK signaling pathway. The expression of genes related to the efficacy of immunotherapy was significantly different between the two groups. A qRT-PCR test verified the expression level of lncRNAs in LUAD cells in the risk model. The AUC of ROC of 5 years in the independent validation dataset showed that this model had superior accuracy. Western blot analysis verified the change of EMT-related marker in protein level.ConclusionThe immune lncRNA risk model established by us could better predict the prognosis of patients with LUAD.
| S-EPMC8044985 | biostudies-literature