Toll-Like Receptor 4 as a Favorable Prognostic Marker in Bladder Cancer: A Multi-Omics Analysis

Abstract

BackgroundThe toll-like receptor 4 (TLR4) agonist, Bacille Calmette-Guérin, has exhibited gratifying effects in treating bladder cancer. The study aims to explore the expression pattern, prognostic value, and potential mechanism of TLR4 in bladder cancer.MethodsThe transcriptome file from the GSE13507 dataset in the Gene Expression Omnibus database and the promoter methylation file from the bladder cancer dataset in The Cancer Genome Atlas database were downloaded for analysis. The prognostic value of the TLRs was assessed by univariate Cox regression. Immunohistochemistry was applied to verify the expression of TLR4 in bladder cancer. The drug response is estimated through the R package “pRRophetic.” The CIBERSORT algorithm was carried out to estimate the infiltrating immune cells of samples. Gene Set Enrichment Analysis (GSEA) was performed to identify the pathways involved under varied TLR4 expression levels.ResultsTLR4 is decreased in tumor tissues compared with surrounding tumor tissues or normal tissue, which is also positively correlated to the overall survival rate (hazard ratio [HR] = 0.38) and cancer-specific survival rate (HR = 0.15) of patients with bladder cancer. Low expression of TLR4 is observed in tumors with malignant performance (high pathological grade, higher tumor stage, and progression). Patients with low TLR4 levels are more sensitive to gemcitabine rather than cisplatin. The promoter methylation level of TLR4 is positively associated with TLR4 expression (P < 0.001). The cg14629571 methylation site largely contributes to the overall methylation level. The CIBERSORT analysis shows that high TLR4 expression is associated with lower levels of plasma cells, M0 macrophages, and M1 macrophages. The GSEA results indicate that the TGF-β pathway and apoptosis are activated in high TLR4 bladder cancer, while G2M checkpoint and E2F targets pathways are enriched in low TLR4 bladder cancer.ConclusionThis research discusses the abnormal expression and prognostic value of TLR4 in bladder cancer. The TLR4 expression can effectively predict oncological outcomes and drug sensitivity of bladder cancer patients. TLR4 is also associated with infiltrating immune cell variation and cancer pathway dysregulation. The results provide a novel prognostic marker and potential drug targets for bladder cancer.

Immunogenic cell death mediation patterns reveal novel paradigm for characterizing the immune microenvironment and immunotherapeutic responses in bladder cancer

“…For example, CALR was more highly-expressed in BCA patients than controls, meanwhile survival analysis showed CALR was a risk factor. So far, the role of TLR4 in BCA has been extensively explored ( Lu et al, 2021 ), consistent with our results showing TLR4 was a protective factor. However, the correlation between BCA and CALR has been rarely reported.…”

A Novel tiRNA-Gly-GCC-1 Promotes Progression of Urothelial Bladder Carcinoma and Directly Targets TLR4

“…TLR4 expression can effectively predict oncological outcomes and drug sensitivity of BLCA patients. TLR4 was also associated with infiltrating immune cell variation and cancer pathway dysregulation [ 28 ]. In another study, researchers found that TLR4 may contribute to immune escape of UBC.…”

Construction of a novel signature and prediction of the immune landscape in gastric cancer based on necroptosis-related genes

“…The half inhibitory concentration (IC50) of chemotherapeutic and targeted therapeutic drugs in different risk groups were calculated by the “pRRophetic” R package 33 , 34 , then we predicted the drugs sensitivity between two risk groups to chemotherapy 35 – 37 . Immunophenoscore (IPS) of the TCGA-GC cohort was downloaded from The Cancer Immunome Atlas (TCIA; https://tcia.at/home ; Table S2 ).…”