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.
Recommended CitationWang, 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; and Galsky, Matthew D., "EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer." (2018). Department of Cancer Biology Faculty Papers. Paper 135.
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