Development of Patient-Derived Lymphoma Tumoroids for Studying Follicular Lymphoma

Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma, demonstrates a strong interplay with its tumor microenvironment (TME), influencing disease progression and therapy resistance, according to data from the 2024 ASH Annual Meeting. To better replicate the TME of FL lymph nodes (LNs), researchers optimized the generation of Patient-Derived Lymphoma Tumoroids (PDLTs). These tumoroids consist of tumor B cells, autologous T cells, and a follicular dendritic cell (FDC) line or a modified variant that mimics germinal center (GC) signals. Embedded in collagen I, a key LN component, PDLTs recreate the cellular and physical environment of FL.

The PDLTs sustain cellular viability for up to 10 days, support proliferation under GC cues, and maintain FL-specific gene expression profiles, as shown by single-cell RNA sequencing. FDC coculture produced gene expression resembling original biopsy samples, while FDC-GC stimuli recapitulated aggressive FL features. Mass spectrometry of the secretome revealed extracellular matrix (ECM) remodeling in high-grade PDLTs, with secretion of collagens, fibronectin, and tenascin C—components associated with FL LNs and transformation.

The researchers tested PDLTs as preclinical models for cell therapy, showing that anti-CD19 CAR-T cells adhered to the tumoroid surface but exhibited limited infiltration and efficacy compared to simpler spheroid models lacking ECM. This highlights ECM as a critical barrier to CAR-T cell penetration, a challenge common in solid tumors.

This patient-derived model successfully recapitulates indolent and aggressive FL features, enabling in vitro studies of FL biology and personalized therapy testing. The study authors note that the system provides insights into structural and cellular TME dynamics, offering a platform for reducing animal use in research.

Reference:

Gimenez R, Serrat N, Castellote-Borrell M, et al. Patient-derived follicular lymphoma tumoroids: A tool to recapitulate biological features of low and high-grade lymphoma. Abstract 1613. Presented ASH 2024. San Diego, CA.