Gene-expression-based T-Cell-to-Stroma Enrichment (TSE) score predicts response to immune checkpoint inhibitors in urothelial cancer

Maud Rijnders, J. Alberto Nakauma-González, Debbie G.J. Robbrecht, Alberto Gil-Jimenez, Hayri E. Balcioglu, Astrid A.M. Oostvogels, Maureen J.B. Aarts, Joost L. Boormans, Paul Hamberg, Michiel S. van der Heijden, Bernadett E. Szabados, Geert J.L.H. van Leenders, Niven Mehra, Jens Voortman, Hans M. Westgeest, Ronald de Wit, Astrid A.M. van der Veldt, Reno Debets*, Martijn P. Lolkema

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Immune checkpoint inhibitors (ICI) improve overall survival in patients with metastatic urothelial cancer (mUC), but therapeutic success at the individual patient level varies significantly. Here we identify predictive markers of response, based on whole-genome DNA (n = 70) and RNA-sequencing (n = 41) of fresh metastatic biopsy samples, collected prior to treatment with pembrolizumab. We find that PD-L1 combined positivity score does not, whereas tumor mutational burden and APOBEC mutagenesis modestly predict response. In contrast, T cell-to-stroma enrichment (TSE) score, computed from gene expression signature data to capture the relative abundance of T cells and stromal cells, predicts response to immunotherapy with high accuracy. Patients with a positive and negative TSE score show progression free survival rates at 6 months of 67 and 0%, respectively. The abundance of T cells and stromal cells, as reflected by the TSE score is confirmed by immunofluorescence in tumor tissue, and its good performance in two independent ICI-treated cohorts of patients with mUC (IMvigor210) and muscle-invasive UC (ABACUS) validate the predictive power of the TSE score. In conclusion, the TSE score represents a clinically applicable metric that potentially supports the prospective selection of patients with mUC for ICI treatment.

Original languageEnglish
Article number1349
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - 14 Feb 2024

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