Claudin-low bladder tumors are immune infiltrated and actively immune suppressed
Jordan Kardos, … , William Y. Kim, Benjamin G. Vincent
Jordan Kardos, … , William Y. Kim, Benjamin G. Vincent
Published March 17, 2016
Citation Information: JCI Insight. 2016;1(3):e85902. https://doi.org/10.1172/jci.insight.85902.
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Research Article Oncology

Claudin-low bladder tumors are immune infiltrated and actively immune suppressed

Abstract

We report the discovery of a claudin-low molecular subtype of high-grade bladder cancer that shares characteristics with the homonymous subtype of breast cancer. Claudin-low bladder tumors were enriched for multiple genetic features including increased rates of RB1, EP300, and NCOR1 mutations; increased frequency of EGFR amplification; decreased rates of FGFR3, ELF3, and KDM6A mutations; and decreased frequency of PPARG amplification. While claudin-low tumors showed the highest expression of immune gene signatures, they also demonstrated gene expression patterns consistent with those observed in active immunosuppression. This did not appear to be due to differences in predicted neoantigen burden, but rather was associated with broad upregulation of cytokine and chemokine levels from low PPARG activity, allowing unopposed NFKB activity. Taken together, these results define a molecular subtype of bladder cancer with distinct molecular features and an immunologic profile that would, in theory, be primed for immunotherapeutic response.

Authors

Jordan Kardos, Shengjie Chai, Lisle E. Mose, Sara R. Selitsky, Bhavani Krishnan, Ryoichi Saito, Michael D. Iglesia, Matthew I. Milowsky, Joel S. Parker, William Y. Kim, Benjamin G. Vincent

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Figure 7

Cytokine and chemokine regulation across bladder cancer subtypes.

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Cytokine and chemokine regulation across bladder cancer subtypes. (A and...
(A and B) Volcano plots of log2 fold change of median gene expression and –log10 P value of gene expression for cytokines and chemokines across claudin-low/basal and claudin-low/luminal subtypes. Dashed lines across plots correspond to P = 0.05. Significance was calculated using Student’s t test with a Bonferroni correction. n = 408. (C) GSEA enrichment plots indicating that NF-κB signatures were decreased in rosiglitazone-treated UMUC7 and UMUC9 bladder cancer cell lines. Significance was determined using GSEA software. (D) Box plots showing that immunosuppression gene signature expression was significantly decreased across UMUC7 and UMUC9 cell lines after rosiglitazone treatment. Significance was determined using Student’s t test. n = 6. (E) Correlation plot of immunosuppression and EMT gene signature expression. n = 408. Significance and correlation were calculated using a Spearman’s rank test. (F) Box plots showing that EMT gene signature expression was decreased across UMUC7 and UMUC9 cell lines after rosiglitazone treatment. Significance was determined using Student’s t test. n = 6. The box plots in D and F denote the interquartile range (IQR), with the box representing Q1 to Q3, the line denoting Q2, and the whiskers extending an additional 1.5 times the IQR beyond Q1 and Q3. The dots represent data points. ES, enrichment score; EMT, epithelial-to-mesenchymal transition; GSEA, gene set enrichment analysis.