AUTHOR=Langfelder Peter , Lin En-Tni , Tsai Yi-Ta , Cha Tai-Lung , Shieh Grace S. 

TITLE=Gene signature for response prediction to immunotherapy and prognostic markers in metastatic urothelial carcinoma

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1607222

DOI=10.3389/fimmu.2025.1607222

ISSN=1664-3224

ABSTRACT=To date, immune checkpoint inhibitors (ICIs) have emerged as a leading treatment for metastatic cancer, significantly improving patient survival while causing relatively few side effects. However, the objective response rate for ICIs remains low approximately 30% in urothelial carcinoma (UC), underscoring the urgent need for predictive response biomarkers. Several state-of-the-art signatures have been revealed in top-tier journals, highlighting the importance of this field. As the number of genes (~20,000) far exceeds the sample sizes of typical training sets (generally ≤ 300), we first developed feature selection procedures to reduce the number of features to a few hundred. We then trained multiple machine learning classifiers using the selected genes and the IMvigor210 dataset, which includes RNA-seq and clinical data from ~298 patients with metastatic UC (mUC). Notably, our predictor LogitDA, using the identified 49-gene signature, achieved a prediction AUC of 0.75 in an independent dataset, PCD4989g(mUC). Moreover, our signature outperformed six state-of-the-art signatures, PD-L1 IHC, and five tumor microenvironment signatures, including IFN-γ, T-effector, and T-cell exhaustion signatures. When we integrated each of the six known signatures with our own, our signature still surpassed the integrated ones in terms of prediction AUC and accuracy in the PCD4989g(mUC) dataset. From our signature, we identified key prognostic biomarkers, with the top five markers LYRM1, RFC4, CENPL, SPAG5, and CACYBP (Benjamini-Hochberg adjusted P < 0.0025) in the IMvigor210 dataset. Finally, we performed pathway analyses using Reactome (MSigDB) and KEGG, to reveal some immune-related pathways enriched such as MHC class II antigen presentation.