In vitro 3D co-culture of mesenchymal stromal cells and Hodgkin Lymphoma cells on Collagen Scaffolds

PURPOSE. Conventional 2D culture systems do not consider the importance of tissue architecture that is particularly relevant since tissue microenvironment deeply contribute to determine the outcome of anti-cancer treatments. In this study we aimed to set up and use an in vitro 3D models for Hodgkin lymphoma (HL) to evaluate the activity of specific ADAM10 inhibitors LT4 and MN8, alone or in combination with the anti-CD30 ADC brentuximab-vedotin (Bre-Ved). METHODS. Three different 3D culture models were set up: mixed spheroids made of HL lymph node (LN) mesenchymal stromal cells (MSC) and Reed Sternberg/Hodgkin lymphoma cells (HL cells), LN-derived de-cellularized matrices and collagen sponges repopulated with both LN-MSC and HL cells. RESULTS AND DISCUSSION. In these 3D systems LT4 and MN8 reduced the size of mixed spheroids and intracellular ATP content. In addition, sCD30 and TNFα shedding was limited by LT4 and MN8 that not only interfered with HL cell growth, but also enhanced the anti-lymphoma effect of Bre-Ved. This effect was evident at low and ineffective doses of Bre-Ved as well, indicating a possible synergistic scheme to potentiate ADC-based lymphoma therapy. CONCLUSIONS. Both direct and combined anti-lymphoma effect of ADAM10 inhibitors with Bre-Ved can be studied in in vitro 3D model recapitulating features of LN microenvironment and leading to ADC effects improvement. For this reason, scaffolds may represent a new promising tool to reproduce LN architecture and useful for the study of pharmacological response.