Molecular Drivers of the Non-T-cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer

Cancer Immunol Res. 2016 Jul;4(7):563-8. doi: 10.1158/2326-6066.CIR-15-0274. Epub 2016 May 17.


Muscle-invasive urothelial bladder cancer is a common malignancy with poor outcomes for which immune checkpoint blockade is now showing promise. Despite clinical activity of PD-1/PD-L1-targeted therapy in this disease, most patients do not benefit and resistance mechanisms remain unknown. The non-T-cell-inflamed tumor microenvironment correlates with poor prognosis and resistance to immunotherapies. In this study, we determined tumor-oncogenic pathways correlating with T-cell exclusion. We first establish in this report that T-cell-inflamed bladder tumors can be identified by immune gene expression profiling with concordance with CD8(+) T-cell infiltration. Upregulation of genes encoding immune checkpoint proteins PD-L1, IDO, FOXP3, TIM3, and LAG3 was associated with T-cell-inflamed tumors, suggesting potential for sensitivity to checkpoint blockade. β-Catenin, PPAR-γ, and FGFR3 pathways were activated in non-T-cell-inflamed tumors. No difference was seen in overall somatic mutational density between groups. The three pathways identified represent targetable potential pathways of tumor-intrinsic immunotherapy resistance. Cancer Immunol Res; 4(7); 563-8. ©2016 AACR.

MeSH terms

  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • Cluster Analysis
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Humans
  • Immunomodulation / genetics
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Mutation
  • PPAR gamma / metabolism
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Tumor Microenvironment / genetics*
  • Tumor Microenvironment / immunology*
  • Urinary Bladder Neoplasms / etiology*
  • Urinary Bladder Neoplasms / metabolism*
  • Urinary Bladder Neoplasms / pathology
  • beta Catenin / metabolism


  • B7-H1 Antigen
  • PPAR gamma
  • Programmed Cell Death 1 Receptor
  • beta Catenin
  • Receptor, Fibroblast Growth Factor, Type 3