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 6

Predicted neoantigen burden by bladder cancer subtype.

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Predicted neoantigen burden by bladder cancer subtype. (A) Stacked bar p...
(A) Stacked bar plot showing the number of predicted neoantigens in each bladder tumor with a predicted IC50 of less than 50 nm (red bars) and less than 150 nm (yellow bars). Numbers of predicted neoantigens are shown in the left y axis. Blue line and right y axis show the number of missense mutations per tumor. n = 289. (B) Scatter plot of somatic missense mutations (log2) versus predicted neoantigen burden (log2) across TCGA data set. Significance and correlation were determined using Spearman’s rank test. n = 289. (C) Box plot showing the number of predicted neoantigens with an IC50 of less than 50 nm by tumor molecular subtype. Subtypes were not significantly different (P > 0.05). Significance was determined by 1-way ANOVA. n = 289. The box plots 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. (D) Kaplan-Meier plot showing survival of bladder cancer patients with high (greater than median value, blue line) versus low (less than median value, red line) predicted numbers of neoantigens. Vertical hash marks indicate censored data. Significance was determined by log-rank test. n = 289. TCGA, The Cancer Genome Atlas.