Abstract
Background: Immunotherapy has recently shown remarkable efficacy for advanced bladder cancer patients. Accordingly, identifying a biomarker associated with the programmed cell death protein 1 (PD-1)/its ligand (PD-L1) genomic signature to predict patient prognosis is necessary. Methods: In this study, we used mutation data and RNA-seq data of bladder cancer samples acquired from The Cancer Genome Atlas (TCGA) database to combine PD-1/PD-L1-associated mutational signatures with PD-1/PD-L1-associated differentially expressed genes (DEGs). Then, we performed a Kaplan-Meier analysis on the corresponding clinical data of the TCGA bladder urothelial carcinoma (BLCA) cohort to identify prognostic genes, and the results were validated using the GSE48075 cohort. The online platform UCSC Xena was used to analyze the relationship between the candidate genes and clinical parameters. We utilized the Human Protein Atlas (HPA) database to validate the protein expression levels. Then, correlation analysis, cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) analysis, and gene set enrichment analysis (GSEA) were used to clarify the mechanism. Results: We identified one prognostic gene, sortilin related receptor 1 (SORL1), whose downregulation was associated with a comparatively advanced BLCA stage. While further exploring this finding, we found that SORL1 expression was negatively correlated with PD-1/PD-L1 expression and M2 macrophage levels. Furthermore, we found that the downregulation of SORL1 expression was significantly associated with a higher epithelial-mesenchymal transition (EMT) score. Conclusion: We described a novel PD-1/PD-L1-associated signature, SORL1, that predicts favorable outcomes in bladder cancer. SORL1 might reduce immune suppression and inhibit the M2 macrophage-induced EMT phenotype of tumor cells.
Highlights
Bladder urothelial carcinoma (BLCA) remains the 10th most commonly diagnosed malignancy globally (Sung et al, 2021)
We identified a novel genomic signature—sortilin related receptor 1 (SORL1) that was closely related to immune microenvironment and predicted favorable outcomes in bladder cancer by exploiting public database
To identify immune-relevant biomarkers that can predict the prognosis of bladder carcinoma, we explored PD-1/PD-L1-relevant genomic profiles in bladder cancer
Summary
Bladder urothelial carcinoma (BLCA) remains the 10th most commonly diagnosed malignancy globally (Sung et al, 2021). The mortality rate of bladder cancer has been decreasing in recent years due to improvements in treatments, immunotherapy as a representative. An immune checkpoint inhibitor (ICI) is a powerful weapon for activating therapeutic antitumor immunity (Pardoll, 2012). Antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death protein 1 (PD-1) and its ligand (PD-L1) target immune checkpoints and activate immune cells to better fight cancers, such as melanoma (Robert et al, 2015; Marzagalli et al, 2019) and non-small-cell lung cancer (NSCLC) (Fehrenbacher et al, 2016; Sun et al, 2020). Immunotherapy has recently shown remarkable efficacy for advanced bladder cancer patients. Identifying a biomarker associated with the programmed cell death protein 1 (PD-1)/its ligand (PD-L1) genomic signature to predict patient prognosis is necessary
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