We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer.
- Authors
Wang, Li; Saci, Abdel; Szabo, Peter M.; Chasalow, Scott D.; Castillo-Martin, Mireia; Domingo-Domenech, Josep; Siefker-Radtke, Arlene; Sharma, Padmanee; Sfakianos, John P.; Gong, Yixuan; Dominguez-Andres, Ana; Oh, William K.; Mulholland, David; Azrilevich, Alex; Hu, Liangyuan; Cordon-Cardo, Carlos; Salmon, Hélène; Bhardwaj, Nina; Zhu, Jun; Galsky, Matthew D.
- 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. Although T-cell infiltration is correlated with EMT-related gene expression in urothelial cancer specimens, here, the authors report EMT-related signatures in urothelial cancer arise mainly from stromal cells. Increased EMT-related gene expression in T-cell infiltrated tumors is associated with an attenuated response to immune checkpoint blockade, providing a rationale for therapeutic co-targeting PD-1 and stromal elements.
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-05992-x