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 5

BCR and TCR segment expression is prognostic.

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BCR and TCR segment expression is prognostic. (A) Number of TCR gene seg...
(A) Number of TCR gene segments by subtype in which increased expression was significantly associated with improved survival by Cox PH model fit. Null distributions (gray bars) with 95% CIs were generated for each by bootstrap resampling of non-TCR genes and calculation of the number of significant P values that were similarly associated with prolonged survival. n = 292. (B) Number of BCR gene segments by subtype in which increased expression was significantly associated with improved survival by Cox PH model fit. Null distributions (gray bars) with 95% CIs were generated for each by bootstrap resampling of non-TCR genes and calculation of the number of significant P values that were similarly associated with prolonged survival. n = 292. (C) Specific TCR gene segments in which increased expression was significantly associated with improved survival by Cox PH model fit for all tumors (gray boxes), basal tumors (red boxes), claudin-low tumors (green boxes), and luminal tumors (blue boxes). (D) Specific BCR gene segments in which increased expression was significantly associated with improved survival by Cox PH model fit for all tumors (gray boxes), basal tumors (red boxes), claudin-low tumors (green boxes), and luminal tumors (blue boxes). (E) Log base 10 number of reads supporting any BCR V(D)J rearrangement are shown by subtype. n = 181. Mann-Whitney U–Wilcoxon test with an FDR multiple testing correction was used to determine significance. (F) Repertoire diversity by subtype. The box plots in E 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. n = 150. Mann-Whitney U–Wilcoxon test with an FDR multiple testing correction was used to determine significance. BCR, B cell receptor; Cox PH, Cox proportional hazard; TCR, T cell receptor.