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 3

Immune characterization of bladder cancer subtypes.

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Immune characterization of bladder cancer subtypes. (A) Volcano plot of ...
(A) Volcano plot of log2 fold change of median gene expression and –log10 P value of gene expression across bladder tumor subtypes. Dashed line across the plots corresponds to a significance threshold of P = 0.05. n = 408. Significance was calculated using Student’s t test with a Bonferroni correction. (B) Heatmaps of supervised clustering of bladder tumor subtypes across previously identified immune signatures. n = 408. (C) Heatmap of supervised clustering of bladder tumor subtypes across an immune suppression gene signature. n = 408. (D) Box plot of immune suppression gene signature z score across bladder tumor subtypes. n = 408. (E) Box plot of PD-L1 gene expression across the Pan-Cancer tumor types. n = 3,602. (F) Box plot of immune suppression gene signature z scores across the Pan-Cancer tumor types. n = 3,602. 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. BLCA, bladder urothelial carcinoma; BRCA, breast cancer; COAD, colon adenocarcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KIRC, kidney renal clear cell carcinoma; LAML, acute myeloid leukemia; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; OV, ovarian serous cystadenocarcinoma; READ, rectum adenocarcinoma; UCEC, uterine corpus endometrial carcinoma; LUM, luminal; TCGA, The Cancer Genome Atlas; PanCan, Pan-Cancer.