Modeling anti-tumor immune responses using patient-derived melanoma organoids

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.