Identification of Four Immune Subtypes in Bladder Cancer Based on Immune Gene Sets

Tang, Chaozhi; Ma, Jiakang; Liu, Xiuli; Liu, Zhengchun

doi:10.3389/fonc.2020.544610

Cited by 32 publications

(31 citation statements)

References 44 publications

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“…Several studies have reported that the dysfunction of tumorinfiltrating immune cells (TIICs) and immune-related genes is associated with tumor stage, tumor grade and patients' prognoses in BLCA (6)(7)(8)(9)(10)(11)(12), indicating that immune dysregulation may be relevant to malignant progression in this disease. However, the different TIICs involved in NMIBC and MIBC have not been fully identified.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of the Immune Microenvironment Contributes to Malignant Progression and Has Prognostic Value in Bladder Cancer

et al. 2020

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ObjectiveThe malignant progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is common and has detrimental effect on patients. We aimed to elucidate the underlying mechanisms of the malignant progression from an immunological perspective and establish a reliable signature for prognostic prediction and immunotherapeutic strategies.MethodsThe Cell Type Identification by Estimating Relative Subsets of RNA Transcripts algorithm was applied to the GSE32894 data set to identify the different tumor-infiltrating immune cells involved in NMIBC and MIBC. Using weighted gene correlation network analysis, survival analysis and least absolute shrinkage and selection operator Cox analysis, we established an immune prognostic signature (IPS) based on 14 overall survival-associated immune genes in The Cancer Genome Atlas (TCGA). Functional enrichment analyses and nomogram were performed to explore the potential effects and prognostic performance of the IPS. Furthermore, the RNA-sequence data from our center were used to validate the expression levels of the selected immune genes in BLCA samples.ResultsDiverse proportions of macrophage subtypes were observed between NMIBC and MIBC. Patients with high risk scores had a worse prognosis than patients with low risk scores in training (TCGA) and validation data sets (GSE32894, GSE13507, and GSE48277). The IPS was a useful prognostic factor for patients treated with immunotherapy in the IMvigor210 trial. Hallmarks of multiple oncogenic pathways were significantly enriched in the high risk group. A novel nomogram model was established for prognostic predictions. The dysregulated expression of the selected immune genes between NMIBC and MIBC was also validated in BLCA samples.ConclusionDysregulation of the immune microenvironment promoted the malignant progression from NMIBC to MIBC. The IPS can stratify patients into different risk groups with distinct prognoses and immunotherapeutic susceptibility, thus facilitating personalized immunotherapy.

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Section: Introductionmentioning

confidence: 99%

Dysregulation of the Immune Microenvironment Contributes to Malignant Progression and Has Prognostic Value in Bladder Cancer

et al. 2020

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“…Growing evidence suggests that immune cells in TME play vital roles in tumorigenesis. These innate immune cells include macrophages, neutrophils, dendritic cells, innate lymphoid cells, myeloid-derived suppressor cells, and natural killer cells which potentially possess tumour-antagonising or tumour-promoting functions [50][51][52]. Cancer cells exhibited iron ion aggregation in the TME for active proliferation, thus from the perspective of iron homeostasis, regulating ferroptosis could effectively kill tumour cells.…”

Section: Discussionmentioning

confidence: 99%

“…The ConsensusClusterPlus package was used for consensus clustering and molecular subtype screening. In brief, k-means clustering was used, with 50 iterations (each using 80% of the samples) [29]. The best cluster number was determined by the clustering score for the cumulative distribution function (CDF) curve, and the relative changes in the area under the CDF curve were evaluated.…”

Section: Identi Cation Of Thca Subtypes Based On Related Genes Of Fermentioning

confidence: 99%

Identification of Ferroptosis Genes In Immune Infiltration and Prognosis In Thyroid Papillary Carcinoma Using Network Analysis

Lin

Fogarty

et al. 2021

Preprint

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Background: Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. While many patients survive, a portion of PTC cases display high aggressiveness and even develop into refractory differentiated thyroid carcinoma. This may be alleviated by developing a novel model to predict the risk of recurrence. Ferroptosis is an iron-dependent form of regulated cell death (RCD) driven by lethal accumulation of lipid peroxides, is regulated by a set of genes and shows a variety of metabolic changes. To elucidate whether ferroptosis occurs in PTC, we analysed the gene expression profiles of the disease and established a new model for the correlation. Methods: The thyroid carcinoma (THCA) datasets were downloaded from The Cancer Genome Atlas (TCGA), UCSC Xena and MisgDB, and included 502 tumour samples and 56 normal samples. A total of 60 ferroptosis related genes were summarised from MisgDB database. Gene set enrichment analysis (GSEA) and Gene set variation analysis (GSVA) were used to analyse pathways potentially involving PTC subtypes. Single sample GSEA (ssGSEA) algorithm was used to analyse the proportion of 28 kinds of immune cells in the tumour immune infiltration microenvironment in THCA and the hclust algorithm was used to conduct immune typing according to the proportion of immune cells. Spearman correlation analysis was performed on the ferroptosis gene expression and the correlation between immune infiltrating cells proportion. We established the WGCNA to identify genes modules that are highly correlated with the microenvironment of immune invasion. DEseq2 algorithm was further used for differential analysis of sequencing data to analyse the functions and pathways potentially involving hub genes. GO and KEGG enrichment analysis was performed using Clusterprofiler to explore the clinical efficacy of hub genes. Univariate Cox analysis was performed for hub genes combined with clinical prognostic data, and the results was included for lasso regression and constructed the risk regression model. ROC curve and survival curve were used for evaluating the model. Univariate Cox analysis and multivariate Cox analysis were performed in combination with the clinical data of THCA and the risk score value, the clinical efficacy of the model was further evaluated.Results: We identified two subtypes in PTC, using Braf as the major mutation of subtype C1 and NRAS as the major mutation of subtype C2. The proportion of cluster 1 was significantly higher than cluster 2 in ferroptosis signature genes that are positively associated. Subsequent analyses of TME immune cells infiltration indicated cluster 1 was remarkably richer than cluster 2. The risk score of THCA in good performance evaluated by ROC curve and survival curve, in conjunction with univariate Cox analysis and multivariate Cox analysis results based on the clinical data showed that the risk score of the proposed model could be used as an independent prognostic indicator to predict the prognosis of patients with papillary thyroid cancer.Conclusions: Our study found seven crucial genes, including Ac008063.2, Apoe, Bcl3, Acap3, Alox5ap, Atxn2l and B2m, and regulation of apoptosis by parathyroid hormone-related proteins significantly associated with ferroptosis and immune cells in PTC, and we constructed the risk score model which can be used as an independent prognostic index to predict the prognosis of patients with PTC.

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“…Tang et al have recently investigated the gene expression profiles of 29 immune gene sets in three independent databases. Based on single-sample Gene Set Enrichment Analysis (ssGSEA) scores for 29 immune gene sets, they were able to define four immuno-subtypes of bladder cancer (referred to as C1–C4) [ 74 ]. C2 is an immune-infiltrating type showing the highest ssGSEA score and the highest degree of immune infiltration, while C4 is an immune “desert” type with the lowest immune score.…”

Section: Biomarkers For Pd-1/pd-l1 Blockade In Bladder Cancermentioning

confidence: 99%

“…Prediction models estimated that C2 was most sensitive to anti-PD-1 therapies but also conventional chemotherapy with gemcitabine and bleomycin. On the other hand, cisplatin and doxorubicin might be more effective in the C4 subtype [ 74 ].…”

Section: Biomarkers For Pd-1/pd-l1 Blockade In Bladder Cancermentioning

confidence: 99%

Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

López-Beltrán

Cimadamore

Blanca

et al. 2021

Cancers

190

125

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A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.

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Identification of Four Immune Subtypes in Bladder Cancer Based on Immune Gene Sets

Cited by 32 publications

References 44 publications

Dysregulation of the Immune Microenvironment Contributes to Malignant Progression and Has Prognostic Value in Bladder Cancer

Dysregulation of the Immune Microenvironment Contributes to Malignant Progression and Has Prognostic Value in Bladder Cancer

Identification of Ferroptosis Genes In Immune Infiltration and Prognosis In Thyroid Papillary Carcinoma Using Network Analysis

Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

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