Abstract
Background: Bladder urothelial cancer (BLCA) treatment using immune checkpoint inhibitors (IMCIs) can result in long-lasting clinical benefits. However, only a fraction of patients respond to such treatment. In this study, we aimed to identify the relationships between immune cell infiltration levels (ICILs) and IMCIs and identify markers for ICILs.Methods: ICILs were estimated based on single-sample gene set enrichment analysis. The response rates of different ICILs to IMCIs were calculated by combining the ICILs of molecular subtypes in BLCA with the response rates of different molecular subtypes of IMvigor 210 trials to a programmed cell death ligand-1 inhibitor. Weighted gene co-expression network analysis was used to identify modules of interest with ICILs. Functional enrichment analysis was performed to functionally annotate the modules. Screening of key genes and unsupervised clustering were used to identify candidate biomarkers. Tumor IMmune Estimation Resource was used to validate the relationships between the biomarkers and ICILs. Finally, we verified the expression of key genes in molecular subtypes of different response rates for IMCIs.Findings: The basal squamous subtype and luminal infiltrated subtype, which showed low response rates for IMCIs, had the highest levels of immune infiltration. The neuronal subtypes, which showed the highest response rates to IMCIs, had low ICILs. The modules of interest and key genes were determined based on topological overlap measurement, clustering results, and inclusion criteria. Modules highly correlated with ICILs were mainly enriched in immune responses and epithelial–mesenchymal transition. After screening the key genes in the modules, five candidate biomarkers (CD48, SEPT1, ACAP1, PPP1R16B, and IL16) were selected by unsupervised clustering. The key genes were inversely associated with tumor purity and were mostly expressed in the basal squamous subtype and luminal infiltrated subtypes.Interpretation: Patients with high ICILs may benefit the least from treatment with IMCIs. Five key genes could predict ICILs in BLCA, and their high expression suggested that the response rate to IMCIs may decrease.
Highlights
Bladder urothelial cancer (BLCA) is one of the 10 most common malignancies worldwide
Considering the concomitant infiltration of activating and suppressive immune cell types, we investigated whether higher immune cell infiltration levels (ICILs) were correlated with elevation of cytotoxic function
We found that ICILs affected the response rate of immune checkpoint inhibitors (IMCIs), and higher ICILs led to lower response rates
Summary
Bladder urothelial cancer (BLCA) is one of the 10 most common malignancies worldwide. Anti-immune checkpoint therapy has tremendously expanded our knowledge of the immunobiology of cancer. Response rates to immune checkpoint inhibitors (IMCIs) are approximately 20% in both the platinum refractory and previously untreated settings [3]. Tumor immune cell therapy may be the key to combatting cancer; the relationship between immune cell infiltration levels (ICILs) and the therapeutic effects of IMCIs is not clear. Bladder urothelial cancer (BLCA) treatment using immune checkpoint inhibitors (IMCIs) can result in long-lasting clinical benefits. We aimed to identify the relationships between immune cell infiltration levels (ICILs) and IMCIs and identify markers for ICILs
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