RT Journal Article
SR Electronic
T1 Defining the microenvironment landscape of bladder cancer using highly multiplexed spatial genomic and proteomic analysis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 675926
DO 10.1101/675926
A1 Jason W Reeves
A1 Zhaojie Zhang
A1 Zachary K Norgaard
A1 Denise M Zhou
A1 JingJing Gong
A1 Yan Liang
A1 Subhasree Das
A1 Sarah E Warren
A1 Manav Korpal
A1 Margaret L Hoang
A1 Joseph M Beechem
A1 Pavan Kumar
A1 Victoria Rimkunas
YR 2019
UL http://biorxiv.org/content/early/2019/06/21/675926.abstract
AB Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. PD-1 pathway targeting immunotherapies have been approved to treat advanced bladder cancer, but most patients exhibit primary resistance, suggesting that immune evasion mechanisms exist. The PPARγ pathway has been identified as a potential therapeutic target in MIBC that is associated with reduced CD8+ T-cell infiltration and increased resistance to immunotherapies. We comprehensively profiled the tumor microenvironment (TME) in formalin-fixed, paraffin-embedded (FFPE) tissues from a cohort of PPARγhigh (n=13) and PPRARγlow (n=12) MIBC, integrating bulk gene expression, targeted mutation sequencing, immunohistochemistry and multiplex spatial profiling of RNA and protein expression on the GeoMx™ Digital Spatial Profiling (DSP) platform. Molecular subtyping was consistent between traditional methods and GeoMx profiling, and, in this cohort, we observed little evidence of spatial heterogeneity in tumor subtyping. The previously characterized T-cell exclusion phenotype of PPARγhigh MIBC was recapitulated on the GeoMx platform and was further extended to show that this is a general phenomenon across immune cell types, supporting potential combination of PPARγ inhibition with ICIs. Furthermore, we found that while immune cells were excluded from PPARγhigh tumors, the stromal compartment from these tumors was not significantly different than those PPARγlow tumors. By preserving spatial relationships during the GeoMx analysis, we also identify a novel association between lower immune cell expression in the tumors and higher expression of β-catenin in the stroma, and differential expression of other WNT pathway members associated with PPARγ activity.One Sentence Summary A new method for capturing tumor-immune signaling in FFPE tissues explores how the PPARG signaling axis is associated with immune cell exclusion in bladder cancer.