: Defining pre-clinical models is of utmost importance for pleural mesothelioma (PM) to improve prognosis and predict therapeutic response. Using cells isolated from pleural fluid (PF) and diagnostic pleural biopsy (PB), we generated PM patient-derived organoids (PM-PDOs) and reactive-mesothelial (RM)-patient derived organoids (RM-PDO) aiming at assessing the proportion of successful cultures both from PF and PB. We also compared the architectural and immune-histochemical features of PM-PDOs to those of parental tissues and evaluated the PM-PDOs response to chemo-immunotherapy. We obtained 11 successful PM-PDOs from 15 PF/PB (73.3%). The rate of success was higher in epithelioid PM (88.8%) compared to biphasic PM (40.0%) (p=0.175), and when using PF (60.0%) compared to PB (20.0%) (p=0.001). We also obtained 3 RM effective cultures from 6 asbestos-exposed patients (50%) with non-specific pleuritis. Transcriptome analysis identified gene expression profile in PM-PDOs, which differentiate from RM-PDOs. PM-PDOs successfully maintained the histological architecture and molecular markers of their parental tumour tissues. The macrophagic component (CD68+ and CD163+) was an important component in RM-PDOs and was present in all three PM histotypes. Epithelioid PM-PDOs showed resistance to both Cis/PeMtx and pembrolizumab plus peripheral blood mononuclear cells (PBMCs), while both biphasic and sarcomatoid subtypes were sensitive to immunotherapy. Notably, immunotherapy induced an upregulation of PD-L1 expression and activated the STAT3/NF-κB signaling pathway, suggesting a mechanism of immune evasion. PF offers a valuable source of cancer and stromal cells to generate PDO, reinforcing its clinical utility for patients who cannot undergo invasive procedures.
Use of Patient-Derived Organoids for Pleural Mesothelioma 3D modelling
Casalone, Elisabetta;Herman, Elton Jalis;Filomena, Rebecca;Matullo, Giuseppe;
2025-01-01
Abstract
: Defining pre-clinical models is of utmost importance for pleural mesothelioma (PM) to improve prognosis and predict therapeutic response. Using cells isolated from pleural fluid (PF) and diagnostic pleural biopsy (PB), we generated PM patient-derived organoids (PM-PDOs) and reactive-mesothelial (RM)-patient derived organoids (RM-PDO) aiming at assessing the proportion of successful cultures both from PF and PB. We also compared the architectural and immune-histochemical features of PM-PDOs to those of parental tissues and evaluated the PM-PDOs response to chemo-immunotherapy. We obtained 11 successful PM-PDOs from 15 PF/PB (73.3%). The rate of success was higher in epithelioid PM (88.8%) compared to biphasic PM (40.0%) (p=0.175), and when using PF (60.0%) compared to PB (20.0%) (p=0.001). We also obtained 3 RM effective cultures from 6 asbestos-exposed patients (50%) with non-specific pleuritis. Transcriptome analysis identified gene expression profile in PM-PDOs, which differentiate from RM-PDOs. PM-PDOs successfully maintained the histological architecture and molecular markers of their parental tumour tissues. The macrophagic component (CD68+ and CD163+) was an important component in RM-PDOs and was present in all three PM histotypes. Epithelioid PM-PDOs showed resistance to both Cis/PeMtx and pembrolizumab plus peripheral blood mononuclear cells (PBMCs), while both biphasic and sarcomatoid subtypes were sensitive to immunotherapy. Notably, immunotherapy induced an upregulation of PD-L1 expression and activated the STAT3/NF-κB signaling pathway, suggesting a mechanism of immune evasion. PF offers a valuable source of cancer and stromal cells to generate PDO, reinforcing its clinical utility for patients who cannot undergo invasive procedures.
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