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 <i>RB1</i>, <i>EP300</i>, and <i>NCOR1</i> mutations; increased frequency of <i>EGFR</i> amplification; decreased rates of <i>FGFR3</i>, <i>ELF3</i>, and <i>KDM6A</i> mutations; and decreased frequency of <i>PPARG</i> 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 <i>PPARG</i> activity, allowing unopposed <i>NFKB</i> 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.