Cancer Immunol Immunother. 2025 Dec 23;75(1):24. doi: 10.1007/s00262-025-04269-9.
ABSTRACT
Immune checkpoint blockade (ICB) therapy can restore T cell function in tumors, but not all patients benefit, and the mechanisms behind this remain unclear. In this study, we used patient-derived organotypic (PDO) cultures from metastatic melanoma to examine transcriptomic and cellular changes following ex vivo T cell stimulation. Genomic and transcriptomic features were preserved during PDO formation, capturing melanoma heterogeneity. PDOs from ICB-responsive patients showed rapid T cell expansion upon T cell stimulation, unlike those from ICB-resistant tissue. Resistant tissue harbored T cells lacking activation and checkpoint markers, suggesting non-tumor-reactive T cells. A T cell-specific transcriptomic score, activated in responsive PDOs, correlated with improved overall and relapse-free survival in metastatic melanoma patients treated with ICB. These findings demonstrate that ex vivo analysis is a viable tool to investigate mechanisms of ICB response and may help identify predictive biomarkers for patient outcome.
PMID:41432764 | PMC:PMC12728156 | DOI:10.1007/s00262-025-04269-9