Goodbye flat lymphoma biology

B-cell lymphomas grow in aggregates, closely interacting with specific physical elements and cellular environments. While 2D culture systems have long been the standard in the field, current methodologies aim to better replicate lymphoma biology and its microenvironment in 3D. Significant progress has been made since the first 3D lymphoma cell line culture was developed in 2012. Subsequent advances in both cell line and patient-derived systems have incorporated key physical and cellular microenvironmental components. This Review compiles the relevant 3D non-Hodgkin lymphoma models available, outlining their main features, strengths, and limitations. Additionally, we highlight the critical gaps that must be addressed to develop robust, multiplexed, patient-derived B-cell lymphoma systems, which can serve as reliable avatars alongside clinical trials and contribute to the principles of the 3Rs in animal research.

The establishment of 3D models derived from B-lymphoma patient samples in parallel with clinical trials will facilitate the rapid prediction of patient-specific treatment responses and help clinicians identify effective ex vivo drug combinations, ultimately supporting personalized therapeutic decisions for both relapsed and frontline-resistant patients.

3D models of B-cell lymphomas provide a more faithful representation of tumor biology and its microenvironment compared with 2D culture systems. Their development into more complex systems, incorporating vascularization or microfluidics, will not only enhance our understanding of the pathology but also improve the characterization of therapeutic mechanisms in increasingly relevant models. Integrating these systems with clinical approaches will enable better prediction of treatment responses and the ex vivo identification of personalized therapeutic strategies, while reducing reliance on animal models and improving the management of patients who are relapsed or frontline-resistant.

3D non-Hodgkin lymphoma systems established with cell lines or patients samples

Collaborations and partnerships

• Funding: Interreg POCTEFA programme (IMLINFO EFA281/16/), institutional funding (French National Institute of Health and Medical Research, University of Toulouse, and French National Centre for Scientific Research). C. Faria received a doctoral grant from POCTEFA and the French Society of Haematology. C. Dobano-Lopez received a doctoral grant from the Ministry of Economy and Competitiveness.

• Collaboration between the NoLymit team at CRCT and the Microenvironment in Lymphoma Pathogenesis and Therapy team (IDIBAPS, Barcelona)