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Cited by 313Cancer Immunotherapy and BiomarkersBladder and Urothelial Cancer TreatmentsCancer Cells and Metastasis

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

Open access
Wang, Li, Saci, Abdel, Szabo, Peter M., Chasalow, Scott D., Castillo-Martin, Mireia, Domingo-Domenech, Josep, Siefker-Radtke, Arlene, Sharma, Padmanee +12 more·2018·Nature Communications
DOI 10.1038/s41467-018-05992-xPMC PMC6115401
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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.

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  • TME makes great contribution to chemotherapy and immunotherapy sensitivity.

    “Given that TME also makes great contribution to chemotherapy and immunotherapy sensitivity7,19,20”

    From A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients (2021) · cites this paper as [20]

    The Results section reports that T-cell infiltration and EMT/stroma-related gene expression were associated with response to nivolumab in urothelial cancer, supporting the immunotherapy part of the claim. The paper does not establish that the tumor microenvironment determines chemotherapy sensitivity, and its Discussion cautions that the biomarker findings may be prognostic rather than predictive. No page numbers are available in our copy. (LLM, conf=0.86)

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Authors
Wang, L., Saci, A., Szabo, P. M., Chasalow, S. D., Castillo-Martin, M., Domingo-Domenech, J., Siefker-Radtke, A., Sharma, P., Sfakianos, J. P., Gong, Y., Dominguez-Andres, A., Oh, W. K., Mulholland, D., Azrilevich, A., Hu, L., Cordon-Cardo, C., Salmon, H., Bhardwaj, N., Zhu, J., & Galsky, M. D.
Affiliations
  • Sema4 (United States) (US)
  • Bristol-Myers Squibb (United States) (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Tisch Cancer Institute (US)
  • Thomas Jefferson University (US)
Corresponding author
  • Zhu, Jun
  • Galsky, Matthew D.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-08-29
Volume
9
Issue
1
Pages
3503-3503
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-05992-x
PMC
PMC6115401
OpenAlex
W2888172308
Cited by
313
References
49
Citations by year
2026: 18 · 2025: 22 · 2024: 34 · 2023: 42 · 2022: 53 · 2021: 52 · 2020: 61 · 2019: 29 · 2018: 2
FWCI
13.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The Medicine Forum (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Cancer Institute (P30CA196521)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
urothelial carcinoma, epithelial-mesenchymal transition, tumor stroma, anti-PD-1 therapy, immune checkpoint inhibitors, nivolumab, T cell infiltration, immune resistance, gene expression signatures, prognostic factors, metastatic urothelial carcinoma, tumor microenvironment
MeSH terms
Nivolumab, Progression-Free Survival, Animals, Urinary Bladder Neoplasms, Humans, Gene Expression, Genetic Predisposition to Disease, Xenograft Model Antitumor Assays, Mice, Epithelial-Mesenchymal Transition, Programmed Cell Death 1 Receptor

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