Dataset Information

Deciphering the predictive value of senescence-related signature in lung adenocarcinoma: Implications for antitumor immunity and immunotherapy efficacy.

ABSTRACT:

Objective

The senescence process is pivotal in both the onset and advancement of lung adenocarcinoma (LUAD), influencing cell growth, immune evasion, the potential for metastasis, and resistance to treatments. Senescent cells' dual nature, both harmful and advantageous, adds complexity to understanding their expression patterns and clinical relevance in LUAD. In this study, we sought to evaluate the predictive value of the senescence-related signature in survival outcomes and immunotherapy efficacy in patients with LUAD.

Materials and methods

We integrated data from 1449 LUAD cases sourced from different publicly accessible datasets and a clinical cohort of Chinese LUAD patients. The Cox regression analysis employing the least absolute shrinkage and selection operator (LASSO) was performed on 156 senescence-associated genes to develop the senescence-related signature. Kaplan-Meier analysis and time-dependent receiver operating characteristic curves were utilizaed to assess the prognostic significance of the senescence-related signature. Functional annotation, immune infiltration analysis, and gene set variation analysis were applied to investigate the association of the senescence-related signature with anti-tumor immunity in LUAD. Immunotherapy cohorts of non-small cell lung cancer, urothelial carcinoma, skin cutaneous melanoma, and glioblastoma patients were included to assess the senescence-related signature in predicting immunotherapy efficacy.

Results

The senescence-related signature, which encompasses seven senescence-related genes, namely, FOXM1, VDAC1, PPP3CA, MAPK13, PIK3CD, RRAS, and CCND3, was identified to have predictive significance across multiple LUAD cohorts and demonstrated a negative association with antitumor immunity and tumor-infiltrating neutrophils. Patients exhibiting low expression levels of the senescence-related signature responded more favorably to immune checkpoint inhibitors in various solid tumors, including LUAD. Inhibiting FOXM1 pharmacologically with thiostrepton produced tumor-suppressive effects and improved immunotherapy responses in a Lewis lung carcinoma mouse model.

Conclusions

The senescence-related signature demonstrates potential in predicting patient prognosis and immunotherapy efficacy in LUAD.

SUBMITTER: Guo Y

PROVIDER: S-EPMC11357763 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Deciphering the predictive value of senescence-related signature in lung adenocarcinoma: Implications for antitumor immunity and immunotherapy efficacy.

Guo Yufeng Y Wang Yang Y Duan Jianchun J Wan Rui R Chang Geyun G Zhang Xue X Ma Zixiao Z Bai Hua H Wang Jie J

Heliyon 20240808 16

<h4>Objective</h4>The senescence process is pivotal in both the onset and advancement of lung adenocarcinoma (LUAD), influencing cell growth, immune evasion, the potential for metastasis, and resistance to treatments. Senescent cells' dual nature, both harmful and advantageous, adds complexity to understanding their expression patterns and clinical relevance in LUAD. In this study, we sought to evaluate the predictive value of the senescence-related signature in survival outcomes and immunothera ...[more]

PMID: 39211916

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Project description:BackgroundImmune checkpoint inhibitors (ICIs) have been shown to significantly improve the survival of patients with advanced lung adenocarcinoma (LUAD). However, only limited proportion of patients could benefit from ICIs. Novel biomarkers with strong predictability are needed for clinicians to maximize the efficacy of ICIs. Our study aimed to identify potential biomarkers predicting ICIs efficacy in LUAD.MethodsThe Cancer Genome Atlas (TCGA) PanCancer Atlas studies in cBioportal were used to evaluate the mutation frequency of ANK2 across multiple cancers. Clinical and mutational data for LUAD from ICIs-treated cohorts (Hellmann et al. and Rizvi et al.) were collected to explore the correlation between ANK2 mutation and clinical outcomes. In addition, the relationship between ANK2 expression and clinical outcomes was analyzed using LUAD data from TCGA and Gene Expression Omnibus. Furthermore, the impact of ANK2 mutation and expression on the tumor immune microenvironment of LUAD was analyzed using TCGA and TISIDB databases.ResultsPatients with ANK2 mutation benefited more from ICIs. In ICIs-treated cohort, prolonged progression-free survival (PFS) (median PFS: NR (not reached) vs. 5.42 months, HR (hazard ratio) 0.31, 95% CI 0.18-0.54; P = 0.0037), improved complete response rate (17.65% vs. 1.85%, P = 0.0402), and improved objective response rate (64.71% vs. 24.07%, P = 0.0033) were observed in LUAD patients with ANK2 mutation compared to their wild-type counterparts. Regarding ANK2 expression, it was observed that ANK2 expression was decreased in LUAD (P < 0.05) and a higher level of ANK2 expression was associated with longer overall survival (HR 0.69, 95% CI 0.52-0.92; P = 0.012) in TCGA LUAD cohort. Moreover, ANK2 mutation or higher ANK2 expression correlated with enhanced antitumor immunity and "hot" tumor microenvironment in LUAD, which could be potential mechanisms that ANK2 mutation facilitated ICIs therapy and patients with higher ANK2 expression survived longer.ConclusionOur findings suggest that ANK2 mutation or increased ANK2 expression may serve as a favorable biomarker for the efficacy of ICIs in patients with LUAD.

Project description:Background: Cellular senescence is a novel hallmark of cancer associated with patient outcomes and tumor immunotherapy. However, the value of cellular senescence-related long non-coding RNAs (lncRNAs) in predicting prognosis and immunotherapy response for stomach adenocarcinoma (STAD) patients needs further investigation. Methods: The transcriptome and corresponding clinical information of STAD and cellular senescence-related genes were, respectively, downloaded from the Cancer Genome Atlas (TCGA) and CellAge databases. Differential expression analysis and coexpression analysis were performed to obtain cellular senescence-related lncRNAs. Univariate regression analysis and least absolute shrinkage and selection operator (LASSO) Cox analysis were conducted to establish the cellular senescence-related lncRNA prognostic signature (CSLPS). Next, the survival curve, ROC curve, and nomogram were developed to assess the capacity of predictive models. Moreover, principal component analysis (PCA), gene set enrichment analysis (GSEA), tumor microenvironment (TME), tumor mutation burden (TMB), microsatellite instability (MSI), and tumor immune dysfunction and exclusion (TIDE) score analysis were performed between high- and low-risk groups. Results: A novel CSLPS involving fifteen lncRNAs (REPIN1-AS1, AL355574.1, AC104695.3, AL033527.2, AC083902.1, TYMSOS, LINC00460, AC005165.1, AL136115.1, AC007405.2, AL391152.1, SCAT1, AC129507.1, AL121748.1, and ADAMTS9-AS1) was developed. According to the nomogram, the risk model based on the CSLPS was an independent prognostic factor and could predict 1-, 3-, and 5-year overall survival for STAD patients. GSEA suggested that the high-risk group was mainly associated with Toll-like receptor, JAK/STAT, NOD-like receptor, and chemokine signaling pathways. Further analysis revealed that STAD patients in the low-risk group with better clinical outcomes had a higher TMB, higher proportion of high microsatellite instability (MSI-H), better immune infiltration, and lower TIDE scores. Conclusion: A fifteen-CSlncRNA prognostic signature could predict survival outcomes, and patients in the low-risk group may be more sensitive to immunotherapy.

Dataset Information

Deciphering the predictive value of senescence-related signature in lung adenocarcinoma: Implications for antitumor immunity and immunotherapy efficacy.

Objective

Materials and methods

Results

Conclusions

Publications

Deciphering the predictive value of senescence-related signature in lung adenocarcinoma: Implications for antitumor immunity and immunotherapy efficacy.

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