LCK and CD3E Orchestrate the Tumor Microenvironment and Promote Immunotherapy Response and Survival of Muscle-Invasive Bladder Cancer Patients

Background: Studies have demonstrated the significance of multiple biomarkers for bladder cancer. Here, we attempt to present biomarkers potentially predictive of the prognosis and immunotherapy response of muscle-invasive bladder cancer (MIBC).Method: Immune and stromal scores were calculated for MIBC patients from The Cancer Genome Atlas (TCGA). Core differential expression genes (DEGs) with prognostic value were identified and validated using an independent dataset GSE31684. The clinical implications of prognostic genes and the inter-gene correlation were presented. The distribution of tumor-infiltrating immune cells (TICs), the correlation with tumor mutation burden (TMB), and the expression of eight immune checkpoint–relevant genes and CD39 were accordingly compared. Two bladder cancer cohorts (GSE176307 and IMvigor210) receiving immunotherapy were recruited to validate the prognostic value of LCK and CD3E for immunotherapy.Results: 361 MIBC samples from TCGA revealed a worse overall survival for higher stromal infiltration (p = 0.009) but a better overall survival for higher immune infiltration (p = 0.042). CD3E and LCK were independently validated by TCGA and GSE31684 to be prognostic for MIBC. CD3E was the most correlative gene of LCK, with a coefficient of r = 0.86 (p < 0.001). CD8+ T cells and macrophage M1 are more abundant in favor of a higher expression of CD3E and LCK in MIBC and across pan-cancers. Immune checkpoints like CTLA4, CD274 (PD-1), and PDCD1 (PD-L1) were highly expressed in high-CD3E and high-LCK groups for MIBC and also for pan-cancers, except for thymoma. LCK and CD3E had a moderate positive correlation with CD39 expression. Importantly, high-LCK and high-CD3E groups had a higher percentage of responders than the low-expression groups both in GSE176307 (LCK: 22.73vs. 13.64%, CD3E: 22.00 vs. 13.16%) and IMvigor210 cohorts (LCK: 28.19 vs. 17.45%, CD3E: 25.50 vs. 20.13%).Conclusion: CD3E and LCK were potential biomarkers of MIBC. CD3E and LCK were positively correlated with several regular immunotherapy biomarkers, which is supported by real-world outcomes from two immunotherapy cohorts.

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A Novel DNA Methylation Signature as an Independent Prognostic Factor in Muscle-Invasive Bladder Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.614927 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhijie Xu ◽

Hemant Gujar ◽

Guanghou Fu ◽

Hamed Ahmadi ◽

Sumeet Bhanvadia ◽

...

Keyword(s):

Dna Methylation ◽

Overall Survival ◽

Bladder Cancer ◽

Prognostic Factor ◽

The Cancer Genome Atlas ◽

Invasive Bladder Cancer ◽

Clinicopathologic Features ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive ◽

Testing Set

BackgroundMuscle-invasive bladder cancer (MIBC) accounts for approximately 20% of all urothelial bladder carcinomas (UBC) at time of diagnosis, and up to 30% of patients with non-muscle invasive UBC will progress to MIBC over time. An increasing body of evidence has revealed a strong correlation between aberrant DNA methylation and tumorigenesis in MIBC.ResultsUsing The Cancer Genome Atlas (TCGA) molecular data for 413 patients, we described a DNA methylation-based signature as a prognostic factor for overall survival (OS) in MIBC patients. By using a least absolute shrinkage and selection operator (LASSO) model, differentially methylated regions were first identified using multiple criteria followed by survival and LASSO analyses to identify DNA methylation probes related to OS and build a classifier to stratify patients with MIBC. The prognostic value of the classifier, referred to as risk score (RS), was validated in a held-out testing set from the TCGA MIBC cohort. Finally, receiver operating characteristic (ROC) analysis was used to compare the prognostic accuracy of the models built with RS alone, RS plus clinicopathologic features, and clinicopathologic features alone. We found that our seven-probe classifier-based RS stratifies patients into high- and low-risk groups for overall survival (OS) in the testing set (n = 137) (AUC at 3 years, 0.65; AUC at 5 years, 0.65). In addition, RS significantly improved the prognostic model when it was combined with clinical information including age, smoking status, Tumor (T) stage, and Lymph node metastasis (N) stage.ConclusionsThe DNA methylation-based RS can be a useful tool to predict the accuracy of preoperative and/or post-cystectomy models of OS in MIBC patients.

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Integrative multi-omics analysis of muscle-invasive bladder cancer identifies prognostic biomarkers for frontline chemotherapy and immunotherapy

Communications Biology ◽

10.1038/s42003-020-01491-2 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Qianxing Mo ◽

Roger Li ◽

Dennis O. Adeegbe ◽

Guang Peng ◽

Keith Syson Chan

Keyword(s):

Overall Survival ◽

Bladder Cancer ◽

Clustering Analysis ◽

Prognostic Value ◽

Invasive Bladder Cancer ◽

Expression Data ◽

Muscle Invasive Bladder Cancer ◽

Lower Response Rate ◽

Muscle Invasive

AbstractOnly a subgroup of patients with muscle-invasive bladder cancer (MIBC) are responders toward cisplatin-based chemotherapy and PD-L1 blockade immunotherapy. There is a clinical need to identify MIBC molecular subtypes and biomarkers for patient stratification toward the therapies. Here, we performed an integrative clustering analysis of 388 MIBC samples with multi-omics data and identified basal and luminal/differentiated integrative subtypes and derived a 42 gene panel for classification of MIBC. Using nine additional gene expression data (n = 844), we demonstrated the prognostic value of the 42 basal-luminal genes. The basal subtype was associated with worse overall survival in patients receiving no neoadjuvant chemotherapy (NAC), but better overall survival in patients receiving NAC in two clinical trials. Each of the subtypes could be further divided into chr9 p21.3 normal or loss subgroup. The patients with low expression of MTAP/CDKN2A/2B (indicative of chr9 p21.3 loss) had a significantly lower response rate to anti-PD-L1 immunotherapy and worse survival than the patients with high expression of MTAP/CDKN2A/2B. This integrative analysis reveals intrinsic MIBC subtypes and biomarkers with prognostic value for the frontline therapies.

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Exploration of Prognostic Biomarkers of Muscle-Invasive Bladder Cancer (MIBC) by Bioinformatics

Evolutionary Bioinformatics ◽

10.1177/11769343211049270 ◽

2021 ◽

Vol 17 ◽

pp. 117693432110492

Author(s):

Xianglai Xu ◽

Yelin Wang ◽

Sihong Zhang ◽

Yanjun Zhu ◽

Jiajun Wang

Keyword(s):

Bladder Cancer ◽

Characteristic Curve ◽

Prognostic Index ◽

The Cancer Genome Atlas ◽

Invasive Bladder Cancer ◽

Immune Checkpoints ◽

Venn Diagram ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive ◽

Cox Analysis

We aimed to discover prognostic factors of muscle-invasive bladder cancer (MIBC) and investigate their relationship with immune therapies. Online data of MIBC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database (GEO) database. Weighted gene co-expression network analysis (WGCNA) and univariate Cox analysis were applied to classify genes into different groups. Venn diagram was used to find the intersection of genes, and prognostic efficacy was proved by Kaplan-Meier analysis. Heatmap was utilized for differential analysis. Riskscore (RS) was calculated according to multivariate Cox analysis and evaluated by receiver operating characteristic curve (ROC). MIBC samples from TCGA and GEO were analyzed by WGCNA and univariate Cox analysis and intersected at 4 genes, CLK4, DEDD2, ENO1, and SYTL1. Higher SYTL1 and DEDD2 expressions were significantly correlated with high tumor grades. Riskscore based on genes showed great prognostic efficiency in predicting overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in TCGA dataset ( P < .001). The area under the ROC curve (AUC) of RS reached 0.671 in predicting 1-year survival and 0.653 in 3-year survival. KEGG pathways enrichment filtered 5 enriched pathways. xCell analysis showed increased T cell CD4+ Th2 cell, macrophage, macrophage M1, and macrophage M2 infiltration in high RS samples ( P < .001). In immune checkpoints analysis, PD-L1 expression was significantly higher in patients with high RS. We have, therefore, constructed RS as a convincing prognostic index for MIBC patients and found potential targeted pathways.

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