Abstract
Malignant mesothelioma (MM) is a rare, aggressive cancer with poor outcomes due to its heterogeneity and therapy resistance. Patient-derived organoids (PDOs) have emerged as a promising tool for precision medicine, as they faithfully recapitulate key tumor characteristics. This study aimed to establish MM PDOs and develop a PDO-T cell co-culture system to evaluate their utility in guiding personalized MM treatment. MM PDOs were generated from malignant ascites, pleural effusions, fine-needle biopsies, and surgical tissues. Organoids were characterized using H&E staining, immunohistochemistry (IHC), and next-generation sequencing (NGS). PBMC-derived T cells were co-cultured with PDOs to assess immunotherapy and chemotherapy responses. Drug sensitivity testing was performed to evaluate treatment efficacy. 11 MM PDOs were successfully established, which recapitulated the histological features and genomic profiles of their parental tumors. Drug sensitivity testing revealed heterogeneous responses of PDOs, with sensitivity to anlotinib but resistance to cisplatin plus pemetrexed plus bevacizumab. Notably, PDOs established from the same patient at different time points displayed dynamic changes in genetic profiles and drug sensitivities, mirroring in vivo tumor progression. In the PDO-T cell co-culture system, anti-PD-1 immunotherapy, especially combined with chemotherapy, significantly reduced organoids viability of patient PM002. MM PDOs and the PDO-T cell co-culture system constitute robust models for investigating tumor progression, drug responses, and immunotherapy efficacy. These tools highlight their potential in advancing personalized medicine for MM.