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

Li Wang, Abdel Saci, Peter M. Szabo, Scott D. Chasalow, Mireia Castillo-Martin, Josep Domingo-Domenech, Arlene Siefker-Radtke, Padmanee Sharma, John P. Sfakianos, Yixuan Gong, Ana Dominguez-Andres, William K. Oh, David Mulholland, Alex Azrilevich, Liangyuan Hu, Carlos Cordon-Cardo, Hélène Salmon, Nina Bhardwaj, Jun Zhu () and Matthew D. Galsky ()
Additional contact information
Li Wang: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Abdel Saci: Bristol-Myers Squibb
Peter M. Szabo: Bristol-Myers Squibb
Scott D. Chasalow: Bristol-Myers Squibb
Mireia Castillo-Martin: Icahn School of Medicine at Mount Sinai
Josep Domingo-Domenech: Sidney Kimmel Cancer Center, Thomas Jefferson University
Arlene Siefker-Radtke: University of Texas MD Anderson Cancer Center
Padmanee Sharma: University of Texas MD Anderson Cancer Center
John P. Sfakianos: Icahn School of Medicine at Mount Sinai
Yixuan Gong: Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute
Ana Dominguez-Andres: Sidney Kimmel Cancer Center, Thomas Jefferson University
William K. Oh: Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute
David Mulholland: Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute
Alex Azrilevich: Bristol-Myers Squibb
Liangyuan Hu: Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute
Carlos Cordon-Cardo: Icahn School of Medicine at Mount Sinai
Hélène Salmon: Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute
Nina Bhardwaj: Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute
Jun Zhu: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Matthew D. Galsky: Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05992-x

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