Development and validation of a model based on immunogenic cell death related genes to predict the prognosis and immune response to bladder urothelial carcinoma.

Immunogenic cell death (ICD) has been categorized as a variant of regulated cell death that is capable of inducing an adaptive immune response. A growing body of evidence has indicated that ICD can modify the tumor immune microenvironment by releasing danger signals or damage-associated molecular patterns (DAMPs), potentially enhancing the efficacy of immunotherapy. Consequently, the identification of biomarkers associated with ICD that can classify patients based on their potential response to ICD immunotherapy would be highly advantageous. Therefore the goal of the study is to better understand and identify what patients with bladder urothelial carcinoma (BLCA) will respond to immunotherapy by analyzing ICD signatures and investigate ICD-related prognostic factors in the context of BLCA. The data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases regarding BLCA and normal samples was categorized based on ICD-related genes (IRGs). Specifically, we conducted an immunohistochemical (IHC) experiment to validate the expression levels of Calreticulin (CALR) in both tumor and adjacent tissues, and evaluated its prognostic significance using the Kaplan-Meier (KM) curve. Subsequently, the samples from TCGA were divided into two subtypes using consensus clustering. To obtain a more comprehensive comprehension of the biological functions, we utilized Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). The calculation of immune landscape between two subtypes was performed through ESTIMATE and CIBERSORT. Risk models were constructed using Cox and Lasso regression and their prognosis predictive ability was evaluated using nomogram, receiver operating characteristic (ROC), and calibration curves. Finally, Tumor Immune Dysfunction and Exclusion (TIDE) algorithms was utilized to predict the response to immunotherapy. A total of 34 IRGs were identified, with most of them exhibiting upregulation in BLCA samples. The expression of CALR was notably higher in BLCA compared to the adjacent tissue, and this increase was associated with an unfavorable prognosis. The differentially expressed genes (DEGs) associated with ICD were linked to various immune-related pathways. The ICD-high subtypes exhibited an immune-activated tumor microenvironment (TME) compared to the ICD-low subtypes. Utilizing three IRGs including CALR, IFNB1, and IFNG, a risk model was developed to categorize BLCA patients into high- and low-risk groups. The overall survival (OS) was considerably greater in the low-risk group compared to the high-risk group, as evidenced by both the TCGA and GEO cohorts. The risk score was identified as an independent prognostic parameter (all p < 0.001). Our model demonstrated good predictive ability (The area under the ROC curve (AUC), AUC1-year= 0.632, AUC3-year= 0.637, and AUC5-year =0.653). Ultimately, the lower risk score was associated with a more responsive immunotherapy group. The potential of the ICD-based risk signature to function as a marker for evaluating the prognosis and immune landscape in BLCA suggests its usefulness in identifying the suitable population for effective immunotherapy against BLCA.

Chen L ，Lin J ，Wen Y ，Chen Y ，Chen CB ... -  《Frontiers in Oncology》

Development of a prognostic model to predict BLCA based on anoikis-related gene signature: preliminary findings.

Zhu S ，Zhao Q ，Fan Y ，Tang C ... -  《BMC Urology》

Prognostic model development and molecular subtypes identification in bladder urothelial cancer by oxidative stress signatures.

Dong Y ，Wu X ，Xu C ，Hameed Y ，Abdel-Maksoud MA ，Almanaa TN ，Kotob MH ，Al-Qahtani WH ，Mahmoud AM ，Cho WC ，Li C ... -  《Aging-US》

Disulfidptosis characterizes the tumor microenvironment and predicts immunotherapy sensitivity and prognosis in bladder cancer.

Bladder cancer (BLCA) is prone to metastasis and has poor prognosis with unsatisfactory treatment responsiveness. Disulfidptosis is a recently discovered, novel mode of cell death that is closely associated with human cancers. However, a comprehensive analysis of the relationship between disulfidptosis and BLCA is lacking. Therefore, this study aimed to explore the potential effect of disulfidptosis on BLCA and identify a biomarker for evaluating the prognosis and immunotherapy of patients with BLCA. We acquired BLCA RNA sequencing data from The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) cohort (containing 19 normal samples and 409 tumor samples) and the GES39281 cohort (containing 94 tumor samples) which were used for external validation of the signature. Initially, we performed unsupervised consensus clustering to explore disulfidptosis-related subgroups. We then conducted functional enrichment analysis on these subgroups to gain insights into their biological significance and evaluate their immunotherapy response and chemotherapy sensitivity. Next, we conducted Least Absolute Shrinkage and Selection Operator (LASSO) regression and multivariate Cox regression to construct a prognostic signature in the TCGA training set for prognosis-related differentially expressed genes (DEGs) in the disulfidptosis-related subgroups. Subsequently, we used a receiver operating characteristic (ROC) curve and independent prognostic analysis to validate the predictive performance of the signature in the TCGA testing and the GES39281 cohorts. Finally, we explored the therapeutic value of this signature in patients with BLCA, in terms of immunotherapy and chemotherapy. In this study, we obtained two subgroups: DRG-high (238 samples) and DRG-low (160 samples). The DRG-high group exhibited a poor survival rate compared to the DRG-low group and had a significant association with tumor grade, stage, and metastasis. Additionally, several pathways related to cancer and the immune system were enriched in the high-DRG group. Moreover, the DRG-high group exhibited higher expression of PD1 and CTLA4 and had a better response to immunotherapy in patients with both PD1 and CTLA4 positivity. Conversely, the DRG-high group was more sensitive to common chemotherapeutic agents. A prognostic signature was created, consisting of COL5A1, DIRAS3, NKG7, and POLR3G and validated as having a robust predictive capability. Patients in the low-risk-score group had more immune cells associated with tumor suppression and better immunotherapy outcomes. This study contributes to our understanding of the characteristics of disulfidptosis-related subgroups in BLCA. Disulfidptosis-related signatures can be used to assess the prognosis and immunotherapy of patients with BLCA.

Pan G ，Xie H ，Xia Y 《Heliyon》

Identification of a novel defined inflammation-related long noncoding RNA signature contributes to predicting prognosis and distinction between the cold and hot tumors in bladder cancer.

Bladder cancer (BLCA) is one of the most frequently diagnosed urological malignancies and is the 4th most common cancer in men worldwide. Molecular targets expressed in bladder cancer (BLCA) are usually used for developing targeted drug treatments. However, poor prognosis and poor immunotherapy efficacy remain major challenges for BLCA. Numerous studies have shown that long non-coding RNAs (LncRNAs) play an important role in the development of cancer. However, the role of lncRNAs related to inflammation in BLCA and their prognostic value remain unclear. Therefore, this study is aimed to explore new potential biomarkers that can predict cancer prognosis. We downloaded BLCA-related RNA sequencing data from The Cancer Genome Atlas (TCGA) and searched for inflammation-related prognostic long non-coding RNAs (lncRNAs) by univariate Cox (uniCox) regression and co-expression analysis. We used the least absolute shrinkage and selection operator (LASSO) analysis to construct an inflammation-related lncRNA prognosis risk model. Samples were divided into high-risk score (HRS) group and low-risk score (LRS) group based on the median value of risk scores. The independent variable factors were identified by univariate Cox (uni-Cox) and multivariate Cox (multi-Cox) regression analyses, and receiver operating characteristic (ROC) curves were used to compare the role of different factors in predicting outcomes. Nomogram and Calibration Plot were generated by the R package rms to analyze whether the prediction results are correct and show good consistency. Correlation coefficients were calculated by Pearson analysis. The Kaplan-Meier method was used to assess the prognostic value. The expression of 7 lncRNAs related with inflammation was also confirmed by qRT-PCR in BLCA cell lines. Kyoto Encyclopedia of Gene and Genome (KEGG) pathways that were significantly enriched (P < 0.05) in each risk group were identified by the GSEA software. The R package pRRophetic was used to predict the IC50 of common chemotherapeutic agents. TIMER, XCELL, QUANTISEQ, MCPCOUNTER, EPIC and CIBERSORT were applied to quantify the relative proportions of infiltrating immune cells. We also used package ggpubr to evaluate TME scores and immune checkpoint activation in LRS and HRS populations. R package GSEABase was used to analyze the activity of immune cells or immune function. Different clusters of principal component analysis (PCA), t-distribution random neighborhood embedding (t-SNE), and Kaplan-Meier survival were analyzed using R package Rtsne's. The R package ConsensesClusterPlus was used to class the inflammation-related lncRNAs. In this study, a model containing 7 inflammation-related lncRNAs was constructed. The calibration plot of the model was consistent with the prognosis prediction outcomes. The 1-, 3-, and 5-year ROC curve (AUC) were 0.699, 0.689, and 0.699, respectively. High-risk patients were enriched in lncRNAs related with tumor invasion and immunity, and had higher levels of immune cell infiltration and immune checkpoint activation. Hot tumors and cold tumors were effectively distinguished by clusters 2 and 3 and cluster 1, respectively, which indicated that hot tumors are more susceptible to immunotherapy. Our study showed that inflammation-related LncRNAs are closely related with BLCA, and inflammation-related lncRNA can accurately predict patient prognosis and effectively differentiate between hot and cold tumors, thus improving individualized immunotherapy for BLCA patients. Therefore, this study provides an effective predictive model and a new therapeutic target for the prognosis and clinical treatment of BLCA, thus facilitating the development of individualized tumor therapy.

Xiong X ，Chen C ，Li X ，Yang J ，Zhang W ，Wang X ，Zhang H ，Peng M ，Li L ，Luo P ... -  《Frontiers in Oncology》