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

L Wang, A Saci, PM Szabo, SD Chasalow… - Nature …, 2018 - nature.com
L Wang, A Saci, PM Szabo, SD Chasalow, M Castillo-Martin, J Domingo-Domenech…
Nature communications, 2018nature.com
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 …
Abstract
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.
nature.com