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.
Highlights
Cancers infiltrated with T-cells are associated with a higher likelihood of response to PD-1/ PD-L1 blockade
The seemingly counterintuitive relationship between epithelial–mesenchymal transition (EMT) and T-cell infiltration, and contradictory clinical implications posed by prior studies, raise several critical questions: What is the cellular origin of EMTrelated gene signatures derived from bulk urothelial cancer (UC) transcriptomes? Does EMT-related gene expression reflect the biological process of EMT? How do EMT-related gene expression and T-cell infiltration together impact outcomes in patients with UC treated with PD-1/PD-L1 blockade?
Using data derived from a large clinical trial of patients with UC treated with the 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
Summary
Cancers infiltrated with T-cells are associated with a higher likelihood of response to PD-1/ PD-L1 blockade. 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. Tumors infiltrated with T-cells, commonly referred to as “hot” tumors, are associated with a higher likelihood of response to immune checkpoint blockade[5,6,7,8,9] These findings have led to the conceptual framework of “hot” vs “cold” tumors as an approach to understanding mechanisms of sensitivity and resistance to treatment[10]. Using data derived from a large clinical trial of patients with UC treated with the 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. Our findings suggest a stroma-mediated source of immune resistance in UC and provide rationale for co-targeting PD-1 and stromal elements
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