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The DUTRENEO trial: bulk prospective biomarker-guided therapy selection and spatial transcriptomic dissection of immunotherapy response in muscle-invasive bladder cancer

ABSTRACT: Predictive biomarkers for immune checkpoint inhibitors (ICI) have largely been identified retrospectively, but their clinical utility remains unproven in prospective settings. Here, we report the results of DUTRENEO, a prospective, randomized phase 2 trial testing whether a retrospective, well-validated, 18-gene tumor inflammation signature (TIS) could guide neoadjuvant ICI therapy in muscle-invasive bladder cancer. The trial failed to meet its primary endpoint, demonstrating that bulk gene expression stratification does not sufficiently enrich for responders in this setting. To understand the biological determinants of this failure, we generated a single-cell spatial transcriptomics dataset profiling 377 genes in ~5.4 million cells across large tissue areas. This high-resolution profiling revealed that response to ICI is governed by spatial architectures invisible to bulk assays, specifically the proximity of CD8⁺ T cells to cancer cells and the localized co-expression of checkpoints within epithelial-rich neighborhoods. Furthermore, we identified fibroblast-rich communities as a key feature of immune exclusion in non-responders. We derived a quantitative framework for the design of future clinical trials incorporating spatial analyses, demonstrating that reducing the annotation panel to ≥77 genes and sampling ≥3 mm tissue diameter preserves predictive spatial signal while enabling scalable throughput. These findings elucidate the architectural constraints that limit bulk biomarkers and provide a quantitative framework to embed spatial profiling into clinical studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328930 | GEO | 2026/04/24

REPOSITORIES: GEO

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Project description:Background Immune checkpoint inhibitor (ICI) has greatly improved the prognosis of advanced melanoma. Whereas the efficacy in Japanese patients has been found to be lower than Caucasian, the genomic and transcriptomic features associated with response to ICI of Japanese melanomas remain to be elucidated. Patients and methods Total 129 tumour samples from 78 melanoma patients, who received therapeutic regimens with or without ICI treatment, were collected at 13 institutions in Japan. We performed exome and RNA sequencing and investigated the association of genomic and transcriptomic factors with clinical efficacy of ICI therapy. Time-course data were also analysed. This is the first and largest genomic cohort study for Japanese melanoma, in which tumour samples were prospectively analysed. Results Number of somatic SNVs of Japanese melanomas is lower than that of TCGA Caucasian data due to the biased distribution of WHO subtypes. Driver subtypes of BRAF, NRAS and NF1 was less prevalent but Triple Wildtype predominantly existed in the Japanese cohort. Whereas exome-wide survey revealed no significant association of mutated genes with ICI response, by transcriptomic analysis we identified inflammation-associated genes including several chemokines and cytokines were highly expressed in responders. Follicular helper T cells estimated by immune-cell composition analysis were found significantly enriched in responders (p = 0.0422). Through time-course transcriptome analysis, in addition to several cytotoxic T-cell genes as previously reported, MARCO on tumour-associated macrophages was found induced by ICI treatment in responders (p = 0.0040). The protein expression of these genes was confirmed by immunohistochemical and multiplex immunofluorescent analyses. Some of these genes can be useful biomarkers for prediction of ICI response in the treatment of Japanese melanoma. Conclusions Through prospective genomic and transcriptomic analyses of Japanese melanoma samples, candidate biomarkers for ICI treatment were identified.

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The DUTRENEO trial: bulk prospective biomarker-guided therapy selection and spatial transcriptomic dissection of immunotherapy response in muscle-invasive bladder cancer

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