Inhibitors of A Disintegrin And Metalloproteinases-10 reduce Hodgkin lymphoma cell growth in 3D microenvironments and enhance brentuximab-vedotin effect

Shedding of A Disintegrin And Metalloproteinases (ADAM10) substrates, like TNFα or CD30, can affect both anti-tumor immune response and antibody-drug-conjugate (ADC)-based immunotherapy. We have published two new ADAM10 inhibitors, LT4 and MN8 able to prevent such shedding in Hodgkin lymphoma (HL). Since tumor tissue architecture deeply influence the outcome of anti-cancer treatments, we set up new three-dimensional (3D) culture systemsto verify whether ADAM10 inhibitors can contribute to, or enhance, the anti-lymphoma effects of the ADC brentuximab-vedotin (BtxVed).To recapitulate some aspects of lymphoma structure and architecture, we assembled two 3D culture models: mixed spheroids made of HL lymph node (LN) mesenchymal stromal cells (MSC) and Reed Sternberg/Hodgkin lymphoma cells (HL cells) or collagen scaffolds repopulated with LN-MSC and HL cells. In these 3D systems we found that: 1) the ADAM10 inhibitors LT4 and MN8 reduce ATP content or glucose consumption, related to cell proliferation, increasing lactate dehydrogenase (LDH) release as a cell damage hallmark; 2) these events are paralleled by mixed spheroids size reduction and inhibition of CD30 and TNFα shedding; 3) the effects observed can be reproduced in repopulated HL LN-derived matrix or collagen scaffolds; 4) ADAM10 inhibitors enhance the antilymphoma effect of the anti-CD30 ADC BtxVed both in conventional cultures and in repopulated scaffolds. Thus, we provide evidence for direct and combined anti-lymphoma effect of ADAM10 inhibitors with BtxVed, leading to improvement of ADC effects; this is documented in 3D models recapitulating features of LN microenvironment, that can be proposed as reliable tool for antilymphoma drug testing.