Bladder Cancer Exhibiting High Immune Infiltration Shows the Lowest Response Rate to Immune Checkpoint Inhibitors
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 level...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2019.01101/full |
| _version_ | 1811324770227060736 |
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| author | Shen Pan Yunhong Zhan Xiaonan Chen Bin Wu Bitian Liu |
| author_facet | Shen Pan Yunhong Zhan Xiaonan Chen Bin Wu Bitian Liu |
| author_sort | Shen Pan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T14:21:22Z |
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| id | doaj.art-e51be6e35b5d4b90959428dd77a31363 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-13T14:21:22Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-e51be6e35b5d4b90959428dd77a313632022-12-22T02:43:29ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-10-01910.3389/fonc.2019.01101460930Bladder Cancer Exhibiting High Immune Infiltration Shows the Lowest Response Rate to Immune Checkpoint InhibitorsShen Pan0Yunhong Zhan1Xiaonan Chen2Bin Wu3Bitian Liu4Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, ChinaDepartment of Urology, Shengjing Hospital of China Medical University, Shenyang, ChinaDepartment of Urology, Shengjing Hospital of China Medical University, Shenyang, ChinaDepartment of Urology, Shengjing Hospital of China Medical University, Shenyang, ChinaDepartment of Urology, Shengjing Hospital of China Medical University, Shenyang, ChinaBackground: 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.https://www.frontiersin.org/article/10.3389/fonc.2019.01101/fullbladder urothelial cancermolecular subtypesingle-sample gene set enrichment analysisweighted gene co-expression network analysisimmune checkpoint inhibitorimmune cell infiltration level |
| spellingShingle | Shen Pan Yunhong Zhan Xiaonan Chen Bin Wu Bitian Liu Bladder Cancer Exhibiting High Immune Infiltration Shows the Lowest Response Rate to Immune Checkpoint Inhibitors Frontiers in Oncology bladder urothelial cancer molecular subtype single-sample gene set enrichment analysis weighted gene co-expression network analysis immune checkpoint inhibitor immune cell infiltration level |
| title | Bladder Cancer Exhibiting High Immune Infiltration Shows the Lowest Response Rate to Immune Checkpoint Inhibitors |
| title_full | Bladder Cancer Exhibiting High Immune Infiltration Shows the Lowest Response Rate to Immune Checkpoint Inhibitors |
| title_fullStr | Bladder Cancer Exhibiting High Immune Infiltration Shows the Lowest Response Rate to Immune Checkpoint Inhibitors |
| title_full_unstemmed | Bladder Cancer Exhibiting High Immune Infiltration Shows the Lowest Response Rate to Immune Checkpoint Inhibitors |
| title_short | Bladder Cancer Exhibiting High Immune Infiltration Shows the Lowest Response Rate to Immune Checkpoint Inhibitors |
| title_sort | bladder cancer exhibiting high immune infiltration shows the lowest response rate to immune checkpoint inhibitors |
| topic | bladder urothelial cancer molecular subtype single-sample gene set enrichment analysis weighted gene co-expression network analysis immune checkpoint inhibitor immune cell infiltration level |
| url | https://www.frontiersin.org/article/10.3389/fonc.2019.01101/full |
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