A TP53-Associated Immune Prognostic Signature for the Prediction of Overall Survival and Therapeutic Responses in Muscle-Invasive Bladder Cancer

Wu, Xiangkun; Lv, Daojun; Cai, Chao; Zhao, Zhijian; Wang, Ming; Chen, Wenzhe; Liu, Yongda

doi:10.3389/fimmu.2020.590618

Cited by 38 publications

(35 citation statements)

References 55 publications

(60 reference statements)

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“…The KEGG analysis of both the TCGA and GEO cohorts identified various similarly enriched biological processes, including human T-cell leukemia virus one infection, fatty acid metabolism, and the biosynthesis of unsaturated fatty acids. These common biological pathways have recently been reported as the major mechanism of ferroptosis (Wu et al, 2020). Interestingly, the high-risk group in both the GEO and TCGA cohorts tended to have a lower concentration of mast cells and T helper cells (p < 0.05).…”

Section: Discussionmentioning

confidence: 75%

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Construction and External Validation of a Ferroptosis-Related Gene Signature of Predictive Value for the Overall Survival in Bladder Cancer

Liu

Meng

et al. 2021

Front. Mol. Biosci.

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Purpose: To identify whether ferroptosis-related genes play predictive roles in bladder cancer patients and to develop a ferroptosis-related gene signature to predict overall survival outcomes.Materials and Methods: We downloaded the mRNA expression files and clinical data of 256 bladder samples (188 bladder tumour and 68 nontumour samples) from the GEO database and 430 bladder samples (411 bladder tumour and 19 nontumour samples) from the TCGA database. A multigene signature based on prognostic ferroptosis-related genes was constructed by least absolute shrinkage and selection operator Cox regression analysis in the GEO cohort. The TCGA cohort was used to validate the ferroptosis-related gene signature. Next, functional enrichment analysis, including both Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses, was performed to elucidate the mechanism underlying the signature. The ssGSEA scores of 16 immune cells and 13 immune-related pathway activities between the high-risk and low-risk groups were also analysed in our study.Results: Thirty-three (67.3%) ferroptosis-related genes were differentially expressed between bladder tumour samples and nontumour samples in the GEO cohort. The intersection of prognostic ferroptosis-related genes and differentially expressed genes identified four prognostic targets, including ALOX5, FANCD2, HMGCR and FADS2. The least absolute shrinkage and selection operator Cox regression successfully built a 4-gene signature: risk score value = esum (each gene’s normalized expression * each gene’s coefficient). Univariate and multivariate Cox regression analyses were performed in both the GEO and TCGA cohorts to test the independent prognostic value of the 4-gene risk signature. Multivariate Cox regression analysis in the GEO cohort identified age (p < 0.001), grade (p = 0.129) and risk score (p = 0.016) as independent prognostic predictors for overall survival. Multivariate Cox regression analysis in the TCGA cohort also identified age (p = 0.002), stage (p < 0.001) and risk score (p = 0.006) as independent prognostic predictors for overall survival. The type II IFN response was determined to be significantly weakened in the high-risk group in both the GEO and TCGA cohorts.Conclusion: We successfully built a ferroptosis-related gene signature of significant predictive value for bladder cancer. These results suggest a novel research direction for targeted therapy of bladder cancer in the future.

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Section: Discussionmentioning

confidence: 75%

“…The inactivation of suppressor genes encoding proteins regulating DNA repair or apoptosis may also be one possible mechanism (Williams, 2004). Various immune-related pathways are also reported to contribute to the occurrence of bladder cancer (Wu et al, 2020;Yan et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Construction and External Validation of a Ferroptosis-Related Gene Signature of Predictive Value for the Overall Survival in Bladder Cancer

Liu

Meng

et al. 2021

Front. Mol. Biosci.

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“…For example, methylation of the PD-L1 promoter predicts survival in colorectal cancers, head and neck squamous cell carcinoma, and acute myeloid leukemia [ 64 , 65 , 66 ]; PD-1-promoter methylation is associated with recurrence-free survival in prostate cancer [ 65 ]; and CTLA-4 methylation correlates to response to anti-PD-1 and anti-CTLA-4 immunotherapy in melanoma [ 67 ]. For instance, a TP53-associated immune prognostic signature (TIPS) is positively correlated with high expression of LAG-3 and other critical immune checkpoint biomarkers in the TCGA cohort [ 68 ].…”

Section: Regulation Of Lag-3 Expressionmentioning

confidence: 99%

Understanding LAG-3 Signaling

Chocarro

Blanco

Zuazo

et al. 2021

IJMS

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Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule comparable to PD-1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. LAG-3 is the third inhibitory receptor to be exploited in human anti-cancer immunotherapies, and it is considered a potential next-generation cancer immunotherapy target in human therapy, right next to PD-1 and CTLA-4. Unlike PD-1 and CTLA-4, the exact mechanisms of action of LAG-3 and its relationship with other immune checkpoint molecules remain poorly understood. This is partly caused by the presence of non-conventional signaling motifs in its intracellular domain that are different from other conventional immunoregulatory signaling motifs but with similar inhibitory activities. Here we summarize the current understanding of LAG-3 signaling and its role in LAG-3 functions, from its mechanisms of action to clinical applications.

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“…Default options were used for all parameters (27). Next, it was notable that the mutations of several crucial genes, including TP53, RB1, ATM, ERBB2, ERCC2, and FANCC, were indicators of the response to chemotherapy in BLCA (25,28). Thus, we compared the mutation rates of these genes in the high-and low-IFITM3 groups.…”

Section: Prediction Of Chemotherapeutic Responsementioning

confidence: 99%

Interferon-Induced Transmembrane Protein 3 Shapes an Inflamed Tumor Microenvironment and Identifies Immuno-Hot Tumors

Cai

Sun

et al. 2021

Front. Immunol.

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Interferon-induced transmembrane protein 3 (IFITM3) is an interferon-induced membrane protein, which has been identified as a functional gene in multiple human cancers. The role of IFITM3 in cancer has been preliminarily summarized, but its relationship to antitumor immunity is still unclear. A pancancer analysis was conducted to investigate the expression pattern and immunological role of IFITM3 based on transcriptomic data downloaded from The Cancer Genome Atlas (TCGA) database. Next, correlations between IFITM3 and immunological features in the bladder cancer (BLCA) tumor microenvironment (TME) were assessed. In addition, the role of IFITM3 in estimating the clinical characteristics and the response to various therapies in BLCA was also evaluated. These results were next confirmed in the IMvigor210 cohort and a recruited cohort. In addition, correlations between IFITM3 and emerging immunobiomarkers, such as microbiota and N6-methyladenosine (m6A) genes, were assessed. IFITM3 was enhanced in most tumor tissues in comparison with adjacent tissues. IFITM3 was positively correlated with immunomodulators, tumor-infiltrating immune cells (TIICs), cancer immunity cycles, and inhibitory immune checkpoints. In addition, IFITM3 was associated with an inflamed phenotype and several established molecular subtypes. IFITM3 expression also predicted a notably higher response to chemotherapy, anti-EGFR therapy, and immunotherapy but a low response to anti-ERBB2, anti-ERBB4, and antiangiogenic therapy. In addition, IFITM3 was correlated with immune-related microbiota and m6A genes. In addition to BLCA, IFITM3 is expected to be a marker of high immunogenicity in most human cancers. In conclusion, IFITM3 expression can be used to identify immuno-hot tumors in most cancers, and IFITM3 may be a promising pancancer biomarker to estimate the immunological features of tumors.

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A TP53-Associated Immune Prognostic Signature for the Prediction of Overall Survival and Therapeutic Responses in Muscle-Invasive Bladder Cancer

Cited by 38 publications

References 55 publications

Construction and External Validation of a Ferroptosis-Related Gene Signature of Predictive Value for the Overall Survival in Bladder Cancer

Construction and External Validation of a Ferroptosis-Related Gene Signature of Predictive Value for the Overall Survival in Bladder Cancer

Understanding LAG-3 Signaling

Interferon-Induced Transmembrane Protein 3 Shapes an Inflamed Tumor Microenvironment and Identifies Immuno-Hot Tumors

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