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Updated: Jan 7, 2026
Author Spotlight: Recreating Melanoma Complexity with Patient-Derived Organoids for Immunotherapy Evaluation
Published on: September 6, 2024
Modeling anti-tumor immune responses using patient-derived melanoma organoids
Kamila Kaminska1,2, Bengt Phung1,2, Jacob Karlström1,2
1Division of Oncology, Department of Clinical Science, Faculty of Medicine, Lund University, Medicon Village, 22185, Lund, Sweden.
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.
Insights
Patient-derived organotypic (PDO) cultures revealed that immune checkpoint blockade (ICB) resistance in melanoma is linked to non-reactive T cells. An activated T cell score in PDOs predicts patient survival with ICB therapy.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint blockade (ICB) therapy shows promise in restoring T cell function against tumors.
- However, patient response to ICB varies, and the underlying mechanisms of resistance are not fully understood.
Purpose of the Study:
- To investigate the mechanisms of ICB response and resistance using patient-derived organotypic (PDO) cultures from metastatic melanoma.
- To identify potential predictive biomarkers for ICB therapy outcomes.
Main Methods:
- Utilized patient-derived organotypic (PDO) cultures from metastatic melanoma.
- Performed ex vivo T cell stimulation to analyze transcriptomic and cellular changes.
- Assessed genomic and transcriptomic features, T cell expansion, activation, and checkpoint markers.
Main Results:
- Genomic and transcriptomic features of melanoma were preserved in PDO cultures.
- PDOs from ICB-responsive patients exhibited rapid T cell expansion post-stimulation, unlike resistant cases.
- ICB-resistant tissues contained T cells lacking activation and checkpoint markers, suggesting a lack of tumor reactivity.
- A T cell-specific transcriptomic score, active in responsive PDOs, correlated with improved survival in ICB-treated metastatic melanoma patients.
Conclusions:
- Ex vivo analysis of PDOs is a viable method to study ICB response mechanisms.
- Non-tumor-reactive T cells contribute to ICB resistance in melanoma.
- A T cell-specific transcriptomic score may serve as a predictive biomarker for ICB therapy efficacy.
