EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer

Nat Commun. 2018 Aug 29;9(1):3503. doi: 10.1038/s41467-018-05992-x.


Cancers infiltrated with T-cells are associated with a higher likelihood of response to PD-1/PD-L1 blockade. Counterintuitively, a correlation between epithelial-mesenchymal transition (EMT)-related gene expression and T-cell infiltration has been observed across tumor types. Here we demonstrate, using The Cancer Genome Atlas (TCGA) urothelial cancer dataset, that although a gene expression-based measure of infiltrating T-cell abundance and EMT-related gene expression are positively correlated, these signatures convey disparate prognostic information. We further demonstrate that non-hematopoietic stromal cells are a major source of EMT-related gene expression in bulk urothelial cancer transcriptomes. Finally, using a cohort of patients with metastatic urothelial cancer treated with a PD-1 inhibitor, nivolumab, we demonstrate that in patients with T-cell infiltrated tumors, higher EMT/stroma-related gene expression is associated with lower response rates and shorter progression-free and overall survival. Together, our findings suggest a stroma-mediated source of immune resistance in urothelial cancer and provide rationale for co-targeting PD-1 and stromal elements.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epithelial-Mesenchymal Transition / genetics
  • Epithelial-Mesenchymal Transition / physiology*
  • Gene Expression / genetics
  • Genetic Predisposition to Disease
  • Humans
  • Mice
  • Nivolumab / therapeutic use
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / metabolism*
  • Progression-Free Survival
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / metabolism*
  • Xenograft Model Antitumor Assays


  • Programmed Cell Death 1 Receptor
  • Nivolumab